Muscle parameters in fragility fracture risk prediction in older adults: A scoping review.

Half of osteoporotic fractures occur in patients with normal/osteopenic bone density or at intermediate or low estimated risk. Muscle measures have been shown to contribute to fracture risk independently of bone mineral density. The objectives were to review the measurements of muscle health (muscle mass/quantity/quality, strength and function) and their association with incident fragility fractures and to summarize their use in clinical practice. This scoping review follows the PRISMA-ScR guidelines for reporting. Our search strategy covered the three overreaching concepts of 'fragility fractures', 'muscle health assessment' and 'risk'. We retrieved 14 745 references from Medline Ovid SP, EMBASE, Web of Science Core Collection and Google Scholar. We included original and prospective studies on community-dwelling adults aged over 50 years that analysed an association between at least one muscle parameter and incident fragility fractures. We systematically extracted 17 items from each study, including methodology, general characteristics and results. Data were summarized in tables and graphically presented in adjusted forest plots. Sixty-seven articles fulfilled the inclusion criteria. In total, we studied 60 muscle parameters or indexes and 322 fracture risk ratios over 2.8 million person-years (MPY). The median (interquartile range) sample size was 1642 (921-5756), age 69.2 (63.5-73.6) years, follow-up 10.0 (4.4-12.0) years and number of incident fragility fractures 166 (88-277). A lower muscle mass was positively/not/negatively associated with incident fragility fracture in 28 (2.0), 64 (2.5) and 10 (0.2 MPY) analyses. A lower muscle strength was positively/not/negatively associated with fractures in 53 (1.3), 57 (1.7 MPY) and 0 analyses. A lower muscle function was positively/not/negatively associated in 63 (1.9), 45 (1.0 MPY) and 0 analyses. An in-depth analysis shows how each single muscle parameter was associated with each fragility fractures subtype. This review summarizes markers of muscle health and their association with fragility fractures. Measures of muscle strength and function appeared to perform better for fracture risk prediction. Of these, hand grip strength and gait speed are likely to be the most practical measures for inclusion in clinical practice, as in the evaluation of sarcopenia or in further fracture risk assessment scores. Measures of muscle mass did not appear to predict fragility fractures and might benefit from further research, on D3-creatine dilution test, lean mass indexes and artificial intelligence methods.

Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

Differential Blood Counts Do Not Consistently Predict Clinical Measurements of Bone Mineral Density and Microarchitecture at Homeostasis.

The hematopoietic stem cell niche constitutes a complex bone marrow (BM) microenvironment. Osteoporosis is characterized by both reduced bone mineral density (BMD) and microarchitectural deterioration, constituting the most frequent alteration of the BM microenvironment. It is unclear to which extent modifications of the BM microenvironment, including in the context of osteoporosis, influence blood cell production. We aimed to describe the association between lumbar spine and total hip BMD and microarchitecture (assessed by trabecular bone score [TBS]) and differential blood counts. Data were collected at two time points from 803 (first assessment) and 901 (second assessment) postmenopausal women participating in the CoLaus/OsteoLaus cohort, a population-based sample in Lausanne, Switzerland. Participants with other active disease or treatment that could influence hematopoiesis or osteoporosis were excluded. Bivariate and multivariate associations between each peripheral blood cell count and BMD or TBS were performed. Additionally, participants in the highest BMD and TBS tertiles were compared with participants in the lowest BMD and TBS tertiles. At first assessment, only neutrophils were significantly different in the lowest BMD and TBS tertile (3.18 ± 0.09 versus 3.47 ± 0.08 G/L, p = 0.028). At the second assessment, leucocytes (5.90 ± 0.11 versus 5.56 ± 0.10 G/L, p = 0.033), lymphocytes (1.87 ± 0.04 versus 1.72 ± 0.04 G/L p = 0.033), and monocytes (0.49 ± 0.01 versus 0.46 ± 0.1 G/L, p = 0.033) were significantly different. Power analysis did not identify quasi-significant associations missed due to sample size. Although significant associations between blood counts and BMD or TBS were found, none was consistent across bone measurements or assessments. This study suggests that, at homeostasis and in postmenopausal women, there is no clinically significant association between the osteoporotic microenvironment and blood production output as measured by differential blood counts. In the context of conflicting reports on the relationship between osteoporosis and hematopoiesis, our study represents the first prospective two time-point analysis of a large, homogenous cohort at steady state. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone Texture Assessment on Lateral VFAs Using the Texture Research Investigational Platform (TRIP) and its Fracture Discrimination Ability.

Texture Research Imaging Platform applies trabecular bone score (TBS) measurement principles to images acquired with multiple modalities to assess bone texture at various skeletal sites. This study aimed to assess the bone texture score in dual-energy X-ray absorptiometry-acquired lateral vertebral fracture assessment (VFA) images (BTSVFA), evaluate its reproducibility, and vertebral fracture discrimination ability. Subjects included 178 VF cases and 178 non-VF controls, 136 women and 42 men in each group, age 55-92 years, from two research centers. Cases and controls were matched for age (±5 years), body mass index (±5 kg/m2) and TBS. All participants underwent dual-energy X-ray absorptiometry TBS assessment from standard posterior-anterior lumbar spine scans and BTSVFA assessment. VF presence was determined using VFA images applying the Genant's method. BTSVFA was lower among fractured women compared to non-fractured (0.626 ± 0.109 vs 0.675 ± 0.099, p < 0.01), but not among men. In a binary logistic regression adjusted for study center and sex, for each SD lower BTSVFA, there was a 40% increase (OR 1.40, 95% CI (1.13-1.74)) in the risk of having a prevalent VF; area under the curve (95% CI) 0.616 (0.557-0.675). Inter-assessor and inter-centers ICCs for BTSVFA measurements were very good; 0.96 (0.64-0.99) and 0.98 (0.95-0.99), respectively. The BTSVFA precision (coefficient of variation) was 2.42%. This feasibility study demonstrates the potential to assess trabecular bone texture in lateral VFA images with good reproducibility. BTSVFA can discriminate between fractured and non-fractured women independent of their age, body mass index and TBS. In conclusion, BTSVFA, a potential trabecular texture assessment that excludes the posterior elements, may have value in fracture prediction or as a novel approach to be further investigated in spine surgery planning.

Risk Factors, Manifestation, and Awareness of Osteoporosis among Patients of Various Specialists in Switzerland: Results of a National Survey.

Osteoporosis is the most common chronic metabolic bone disease, known to be underdiagnosed and undertreated in parts of the Swiss population. Due to expected rise in new fragility fractures, adequate awareness of associated risk factors and diagnostic and therapeutic options will be essential for the management of osteoporosis. We therefore explored these aspects in a nationwide survey of Swiss specialists and their patients. A total of 262 physician questionnaires and 9065 patient questionnaires were analyzed, mainly from general practitioners (64.9%), followed by rheumatologists (16.8%), gynecologists (12.2%), and endocrinologists (6.1%). Around 20% of patients were under medication and/or had a medical condition increasing the risk of osteoporosis. Further risk factors, such as low consumption of calcium-rich foods, smoking, elevated alcohol intake, and insufficient physical activity, were present across regions and medical fields. 53.9% of patients did not take calcium/vitamin D supplements; 3.5% reported having fragility fractures, and 7.3% received treatment for osteoporosis. Only 38.5% of surveyed patients knew of the chronic nature of osteoporosis, indicating rather low awareness in this population. Despite generally perceived relevance of osteoporosis for daily practice, aspects of its prevention and management varied across regions and medical fields. Raising awareness among patients and physicians will be vital for addressing osteoporosis on a national scale.

Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases.

A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow-up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non-vertebral fractures. The pretreatment predictors of the post-treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

"Inflammaging" and bone in the OsteoLaus cohort.

BACKGROUND: "Inflammaging" is a coined term that combines the processes of inflammation (within the normal range) and aging, since chronic, low-grade, systemic inflammation emerges with increasing age. Unlike high-level inflammation, with which deleterious effects on bone no longer need to be demonstrated, it is unclear whether inflammaging exerts deleterious effects on bone too. METHOD: We assessed associations between inflammaging - measured via cytokine levels (high-sensitivity C-reactive protein (hs-CRP); interleukin-1ß (IL-1ß); interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)) - and bone parameters (prevalent and incident fractures, bone mineral density (BMD) and trabecular bone score (TBS)) in 1390 postmenopausal women from the OsteoLaus study. RESULTS: Mean (±SD) age was 64.5 ± 7.6 and mean bone mass index (BMI) 25.9 ± 4.5 kg/m2. Median hs-CRP, IL-1ß, IL-6 and TNF-α were 1.4 pg/ml, 0.57 pg/ml, 2.36 pg/ml and 4.82 pg/ml, respectively. In total, 10.50% of the participants had a prevalent, low-impact fracture; and, after 5-years of follow up, 5.91% had an incident, low-impact fracture. Mean T-score BMD was - 1.09 ± 1.53 for the spine, - 1.08 ± 1.02 for the femoral neck, and - 0.72 ± 0.96 for the total hip. Mean spine TBS was 1.320 ± 0.10. We found a positive association between hs-CRP and BMD at all sites, and between hs-CRP and the TBS, but none of these associations were significant after adjustment. We found no association between prevalent or incident fractures and hs-CRP. No association was found between IL-1ß, IL6 and TNF-α and BMD, TBS or fractures. CONCLUSION: Our results suggest that bone imaging and structure parameters are not associated with the low-grade cytokine levels (within the normal range) observed with inflammaging.

Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage breast cancer under aromatase inhibitors.

PURPOSE: At denosumab discontinuation, bone turnover markers increase and the gained BMD is lost. In postmenopausal osteoporosis, there is an increased risk of spontaneous vertebral fractures (VFs) of about 1 to 10%, rarely described in women under denosumab for aromatase inhibitors (AI)-treated breast cancer. We aim to describe the characteristics of 15 patients under denosumab given for AI-treated early-stage breast cancer that presented VFs at its discontinuation. METHODS: Single-center retrospective case series of 15 patients. We report clinical data, dual X-ray absorptiometry values at denosumab initiation and discontinuation, and serum B-crosslaps dosage at the time of VF occurrence (before denosumab resumption). RESULTS: Fifteen women (66.4 ± 7.1 years at denosumab discontinuation) that received AI for 5.0 ± 0.6 years, denosumab 60 mg for 8.2 ± 2.0 doses, and developed 60 VFs at denosumab discontinuation, were followed for 24.4 ± 9.5 months. Patients suffered from 1 to 11 (mean 4.0 ± 1.9) clinical VFs within 7 to 16 months after last denosumab injection. VFs developed earlier in patients with longer denosumab treatment (R2 = 0.29, p = 0.04) and in patients without osteoporosis before denosumab (9.4 ± 2.0 vs. 13.0 ± 2.0 months; p = 0.005). Serum B-crosslaps at the time of VFs tended to be higher in patients with earlier VFs (R2 = 0.47; p = 0.06) or with longer denosumab treatment (R2 = 0.48; p = 0.06). Denosumab was resumed in all patients, then switched for a bisphosphonate in eight. No new VFs occurred during follow-up. CONCLUSIONS: Despite an apparently low fracture risk, women under denosumab for AI-treated early-stage breast cancer develop spontaneous VFs at denosumab discontinuation. This risk increases with treatment duration and may be prevented by a potent bisphosphonate.

[Multiple Vertebral Fractures after Denosumab Discontinuation: How to Avoid Them?] / Fractures vertébrales multiples à l'arrêt du denosumab: comment les éviter?

Multiple Vertebral Fractures after Denosumab Discontinuation: How to Avoid Them? Abstract. Denosumab is a monoclonal antibody raised against the RANK ligand that inhibits the maturation and activity of osteoclasts. It decreases bone resorption, increases bone density and reduces fracture risk. However, after its discontinuation, a significant rebound effect appears that lasts about two years. It results in increased markers of bone remodeling, a loss of bone density that may be greater than gain, and an increased risk of multiple vertebral fractures. These fractures occur at a frequency of 1 to 10 %. Due to this high risk, denosumab should be a second-line treatment limited to very specific indications. At denosumab discontinuation, in order to limit the rebound effect, the current recommendation is to prescribe a strong bisphosphonate (alendronate, zoledronate) and regularly monitor the bone resorption markers.

Menopausal Hormone Therapy Is Associated With Reduced Total and Visceral Adiposity: The OsteoLaus Cohort.

Context: After menopause, fat mass (FM) and visceral adipose tissue (VAT) increase and nonbone lean body mass (LBM) decreases. Whether menopausal hormone therapy (MHT) reverses these changes remains controversial. Objective: To assess the effect of MHT on FM, VAT, and LBM before and after its withdrawal and evaluate potential confounders. Design: Cross-sectional study. Setting: General community. Patients or Other Participants: Women of the OsteoLaus cohort (50 to 80 years old) who underwent dual-energy X-ray absorptiometry (DXA) with body composition assessment. After we excluded women with estrogen-modifying medications, the 1053 participants were categorized into current users (CUs), past users (PUs), and never users (NUs) of MHT. Intervention: None. Main Outcome Measures: VAT measured by DXA was the primary outcome. We assessed subtotal and android FM, LBM, muscle strength (hand grip), and confounding factors (caloric intake, physical activity, biomarkers). Results: The groups significantly differed in age, NU < CU < PU. Age-adjusted VAT was lower in CUs than NUs (P = 0.03). CUs exhibited lower age-adjusted body mass index (BMI) (-0.9 kg/m2) and a trend for lower FM (-1.3 kg). The 10-year gain of VAT (P < 0.01) and subtotal and android FM (P < 0.05) was prevented in CUs. No difference in LBM or hand grip was detected. No residual effect was detected for PUs, including for early MHT discontinuers. The confounding factors did not significantly differ between groups except for higher caloric intake in PUs compared with NUs. Conclusions: MHT is associated with significantly decreased VAT, BMI, and android FM. No benefit is detected for LBM. The benefits are not preserved in PUs, suggesting caution when MHT is discontinued.

Correlation study between osteoporosis and hematopoiesis in the context of adjuvant chemotherapy for breast cancer.

This retrospective study attempts to establish if a correlation exists between osteoporosis and hematopoiesis before and after adjuvant chemotherapy in the context of non-metastatic breast cancer. Osteoporosis is interpreted both as a direct marker of osteoblastic decline and as an indirect marker of increased bone marrow adiposity within the hematopoietic microenvironment. Patients from the "Centre du Sein" at CHUV (Centre Hospitalier Universitaire Vaudois) undergoing adjuvant chemotherapy were included in this study. Evolution of blood counts was studied in correlation with the osteoporosis status. Toxicity of chemotherapy was coded according to published probability of febrile neutropenia. One hundred forty-three women were included: mean age 52.1 ± 12.5 years, mean BMI (body mass index) 24.4 ± 4.1. BMD (bone mineral density) scored osteoporotic in 32% and osteopenic in 45%. Prior to chemotherapy, BMD was positively correlated with neutrophil (p < 0.001) and thrombocyte (p = 0.01) count; TBS (trabecular bone score) was not correlated with blood count. After the first cycle of chemotherapy, an increase of one point in TBS correlated with a decrease of 57% on the time to reach leucocyte nadir (p = 0.004). There was a positive correlation between BMD and risk of infection (p < 0.001). Our data demonstrates an association between osteoporosis and lower blood counts in a younger cohort than previously published, extending it for the first time to neutrophil counts in females. Our results suggest that the healthier the bone, the earlier the lowest leucocyte count value, prompting further research on this area.

Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO.

Antiosteoporotic drugs are recommended in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density. As first-line treatment most patients are started with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (bisphosphonates, denosumab, oestrogens or selective oestrogen receptor modulators). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation. Based on the available evidence, this position statement will focus on the long-term management of osteoporosis therapy, formulating decision criteria for clinical practice.

Prediction of potentially avoidable readmission risk in a division of general internal medicine.

INTRODUCTION: The 30-day post-discharge readmission rate is a quality indicator that may reflect suboptimal care. The computerised algorithm SQLape® can retrospectively identify a potentially avoidable readmission (PARA) with high sensitivity and specificity. We retrospectively analysed the hospital stays of patients readmitted to the Department of Internal Medicine of the CHUV (Centre Hospitalier Universitaire Vaudois) in order to quantify the proportion of PARAs and derive a risk prediction model. METHOD: All hospitalisations between January 2009 and December 2011 in our division of general internal medicine were analysed. Readmissions within 30 days of discharge were categorised using SQLape®. The impact on PARAs was tested for various clinical and nonclinical factors. The performance of the developed model was compared with the well-validated LACE and HOSPITAL scores. RESULTS: From a total of 11 074 hospital stays, 777 (7%) were followed with PARA within 30 days. By analysing a group of 6729 eligible stays, defined in particular by the patients' returning to their place of residence (home or residential care centre), we identified the following risk factors: ≥1 hospitalisation in the year preceding index admission, Charlson score >1, active cancer, hyponatraemia, length of stay >11 days, prescription of ≥15 different medications during the stay. These variables were used to derive a risk prediction model for PARA with a good discriminatory power (C-statistic 0.70) and calibration (p = 0.69). Patients were then classified as low (16.4%), intermediate (49.4%) or high (34.2%) risk of PARA. The estimated risk of PARA for each category was 3.5%, 8.7% and 19.6%, respectively. The LACE and the HOSPITAL scores were significantly correlated with the PARA risk. The discriminatory power of the LACE (C-statistic 0.61) and the HOSPITAL (C-statistic 0.54) were lower than our model. CONCLUSION: Our model identifies patients at high risk of 30-day PARA with a good performance. It could be used to target transition of care interventions. Nevertheless, this model should be validated on more data and could be improved with additional parameters. Our results highlight the difficulty to generalise one model in the context of different healthcare systems.

Use of Trabecular Bone Score (TBS) as a Complementary Approach to Dual-energy X-ray Absorptiometry (DXA) for Fracture Risk Assessment in Clinical Practice.

Osteoporosis is a common bone disease characterized by low bone mass and altered bone microarchitecture, resulting in decreased bone strength with an increased risk of fractures. In clinical practice, physicians can assess the risk of fracture for a patient based on several risk factors. Some such as age, weight, and history of fractures after 50 years of age, parental fracture, smoking status, and alcohol intake are incorporated into FRAX, an assessment tool that estimates the 10-year probability of hip fracture and major osteoporotic fractures based on the individual's risk factors profile. The diagnosis of osteoporosis is currently based on bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry scans. Among other widely recognized limitations of BMD is that BMD considers only the density of the bone and fails in measuring bone microarchitecture, for which novel techniques, such as trabecular bone score (TBS), have been developed. TBS is a texture parameter related to bone microarchitecture that may provide skeletal information that is not captured from the standard BMD measurement. Several studies have examined the value of TBS on predicting osteoporotic fractures. Our study aimed to summarize a review of the current scientific literature with focus on fracture risk assessment and to present both its findings and its conclusions regarding how and when TBS should be used. The existing literature indicates that low lumbar spine TBS is associated with a history of fracture and the incidence of new fracture. The effect is largely independent of BMD and of sufficient magnitude to enhance risk stratification with BMD. The TBS effect is also independent of FRAX, with likely greatest utility for those individuals whose BMD levels lie close to an intervention threshold. The clinical and scientific evidence supporting the use of TBS, with the ability of this technology to be seamlessly integrated into a daily workflow, makes TBS an attractive and useful clinical tool for physicians to improve patient management in osteoporosis. Further research is ongoing and necessary to further clarify the role of TBS in additional specific disorders.

Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: 9 Clinical Cases Report.

Context: Denosumab inhibits bone resorption, increases bone mineral density, and reduces fracture risk. Denosumab was approved for the treatment of osteoporosis and the prevention of bone loss in some oncological situations. Denosumab discontinuation is associated with a severe bone turnover rebound (BTR) and a rapid loss of bone mineral density. The clinical consequences of the BTR observed after denosumab discontinuation are not known. Cases Description: We report 9 women who presented 50 rebound-associated vertebral fractures (RAVFs) after denosumab discontinuation. A broad biological and radiological assessment excluded other causes than osteoporosis. These 9 cases are unusual and disturbing for several reasons. First, all vertebral fractures (VFs) were spontaneous, and most patients had a high number of VFs (mean = 5.5) in a short period of time. Second, the fracture risk was low for most of these women. Third, their VFs occurred rapidly after last denosumab injection (9-16 months). Fourth, vertebroplasty was associated with a high number of new VFs. All the observed VFs seem to be related to denosumab discontinuation and unlikely to the underlying osteoporosis or osteopenia. We hypothesize that the severe BTR is involved in microdamage accumulation in trabecular bone and thus promotes VFs. Conclusion: Studies are urgently needed to determine 1) the pathophysiological processes involved, 2) the clinical profile of patients at risk for RAVFs, and 3) the management and/or treatment regimens after denosumab discontinuation. Health authorities, physicians, and patients must be aware of this RAVF risk. Denosumab injections must be scrupulously done every 6 months but not indefinitely.

Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry.

BACKGROUND: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. RESULTS: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. CONCLUSIONS: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

Effects of Exemestane and Tamoxifen treatment on bone texture analysis assessed by TBS in comparison with bone mineral density assessed by DXA in women with breast cancer.

We performed an analysis of a substudy of the randomized Tamoxifen Exemestane Adjuvant Multinational trial to determine the effects of exemestane (EXE) and tamoxifen (TAM) adjuvant treatment on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry compared with the trabecular bone score, a novel grey-level texture measurement that correlates with 3-dimensional parameters of bone texture in postmenopausal women with hormone receptor-positive breast cancer for the first time. In total, 36 women were randomized to receive TAM (n = 17) or EXE (n = 19). Patients receiving TAM showed a mean increase of BMD in lumbar spine from baseline of 1.0%, 1.5%, and 1.9% and in trabecular bone score of 2.2%, 3.5%, and 3.3% at 6-, 12-, and 24-mo treatment, respectively. Conversely, patients receiving EXE showed a mean decrease from baseline in lumbar spine BMD of -2.3%, -3.6%, and -5.3% and in trabecular bone score of -0.9%, -1.7%, and -2.3% at 6-, 12-, and 24-mo treatment, respectively. Changes in trabecular bone score from baseline at spine were also significantly different between EXE and TAM: p = 0.05, 0.007, and 0.006 at 6, 12, and 24 mo, respectively. TAM induced an increase in BMD and bone texture analysis, whereas EXE resulted in decreases. The results were independent from each other.