Jean-Jacques Body’s research while affiliated with Université Libre de Bruxelles and other places

Considerable progress has been made in the management of cancer patients in the last decade with the arrival of anti-cancer immunotherapies (immune checkpoint inhibitors) and targeted therapies. As a result, a broad spectrum of cancers, not just hormone-sensitive ones, have seen several patients achieve profound and prolonged remissions, or even cures. The management of medium- and long-term side-effects of treatment and quality of life of patients are essential considerations. This is especially true for bone, as bone fragility can lead to increased fractures and loss of autonomy, ultimately reducing the possibility of resuming physical activity. Physical activity is essential for lasting oncological remission and prevention of fatigue. While the issue of hormone therapies and their association with breast cancer has been recognized for some time, the situation is relatively new with regards to targeted therapies and immunotherapies. This is particularly challenging given the wide range of available targeted therapies and their application to numerous cancer types. This article provides a comprehensive review of the bone effects of the main anti-cancer therapies currently in use. The review goes beyond glucocorticoids and hormone therapies and discusses for each drug category what is known regarding cellular effects, BMD effects, and fracture incidence.

Low serum vitamin D levels have been associated with a variety of health conditions which has led the medical community but also the general population to evaluate vitamin D status quite liberally. Nevertheless, there remain questions about the efficacy and cost-effectiveness of such a broad and untargeted approach. This review therefore aims to summarize the current evidence and recommendations on when and how to evaluate vitamin D status in human health and disease. For the general population, most guidelines do not recommend universal screening but suggest a targeted approach in populations at risk. Also, some guidelines do not even recommend evaluating vitamin D status when vitamin D substitution is indicated anyway, such as in children or patients receiving anti-osteoporosis drugs. In those guidelines that recommend the screening of vitamin D status, serum 25(OH)D levels are universally proposed as the preferred screening tool. However, little attention is given to analytical considerations and almost no guidelines discuss the timing and frequency of screening. Finally, there is the known variability in diagnostic thresholds for defining vitamin D insufficiency and deficiency. Overall, the existing guidelines on the evaluation of vitamin D status differ broadly in screening strategy and screening implementation, and none of these guidelines discusses alternative screening modes, for instance, the vitamin metabolic ratio. Efforts to harmonize these different guidelines are needed to enhance their efficacy and cost-effectiveness.

Objective Bone and muscle diseases are both highly prevalent in aging adults but results from previous studies examining the relationship between sarcopenia and its components with osteoporosis are inconsistent. This study aimed to evaluate the association between sarcopenia and its components with osteoporosis in elderly postmenopausal women. Materials & Methods This study is based on cross-sectional data from the Fracture RISk Brussels Epidemiological Enquiry (FRISBEE), involving 3560 community-dwelling post-menopausal women initially included between 2007 and 2013. Randomly selected subjects were reassessed 10 years after inclusion with an evaluation of body composition by dual X-ray absorptiometry (DXA), with a medical questionnaire and a complete geriatric assessment. The diagnostic criteria for sarcopenia were low muscle mass < 5.5 kg/m2, low muscle strength < 16 kg, and low gait speed < 0.8 m/s according to the European Working Group on Sarcopenia in Older People (EWGSOP2). Osteoporosis was defined by the National Bone Health Alliance Working Group proposed extended criteria including a history of major osteoporotic fracture and high fracture risk. Results Among the 500 women included, with a median age of 77.4 (74.7–81.8) years, 178 (35.6%) were osteoporotic. Significant correlations were shown between sarcopenia components and bone mineral density (BMD) at all sites as well as trabecular bone score (TBS). The strongest correlations were between handgrip strength and distal forearm BMD (r = 0.27; p < 0.001), and between appendicular lean mass index (ALMI) and total hip BMD (r = 0.36; p < 0.001). Significant differences were observed between sub-groups of osteoporotic status: the handgrip strength, short physical performance battery (SPPB) test, gait speed, and ALMI were significantly lower in osteoporotic subjects (p < 0.001). After adjustment for all covariates, handgrip strength and gait speed were still significantly associated with osteoporosis with an odds ratio of 0.92 (0.88–0.97) and 0.33 (0.11–0.96), respectively. Handgrip strength under 16 kg showed a 2.2-fold higher risk of osteoporosis after adjustment for all covariates. Conclusion Sarcopenia, as defined by EWGSOP2, and its components, particularly handgrip strength and gait speed, were significantly associated with osteoporosis. The trabecular bone score, a surrogate for bone microarchitecture, was also significantly associated with all sarcopenia components. Therefore, it should be taken into consideration when evaluating bone health and fracture risk in routine geriatric clinical practice.

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration–time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect–time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.

Only previous glucocorticoid use and rheumatoid arthritis were predictors of an early fracture (< 2 years after inclusion). A shorter ‘time to first fracture’ was not an independent clinical risk factor for imminent fractures.PurposeRisk factors for fragility fractures independent of BMD were assessed in several prediction models. However, predictors of a shorter 'time to first fracture' and its impact on imminent fractures are unknown.Methods We studied the concept of ‘time to first fracture’ in the FRISBEE (“Fracture RIsk Brussels Epidemiological Enquiry”) cohort (3560 postmenopausal women). Validated fractures were divided into 3 groups: first fracture < 2 years, 2–5 years, and > 5 years after inclusion. Factors associated with first fracture risk were evaluated with uni- and multivariate analyses using Cox modeling. We examined ‘time to first fracture’ as a risk factor for imminent fractures in untreated subjects and in those receiving pharmacological treatment.ResultsClassical risk factors (age, prior fracture, fall history and low BMD) were associated with first fracture in all groups. Previous glucocorticoids and rheumatoid arthritis (RA) were predictors for fracture < 2 years. Imminent fractures were similar in subjects with or without osteoporosis treatment, despite a higher estimated 10-year risk of fragility fracture in those treated, suggesting that treatment is efficient. 'Time to first fracture' was not an independent risk factor for imminent fractures.Conclusion Among the risk factors considered, previous glucocorticoid use and RA were predictors for early fracture, consistent with the concept of very high risk. The ‘time to first validated fracture’ was not an independent risk factor for imminent fractures. Patients with a first osteoporotic fracture should thus be considered at very high risk for re-fracture, independent of the 'time to first fracture'.

Objective To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. Design Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. Data sources Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. Eligibility criteria for selecting studies Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. Results The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. Conclusions The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. Systematic review registration PROSPERO CRD42019128391.

Our imminent model was less sensitive but more selective than FRAX® in the choice of treatment to prevent imminent fractures. This new model decreased NNT by 30%, which could reduce the treatment costs. In the Belgian FRISBEE cohort, the effect of recency further decreased the selectivity of FRAX®.PurposeWe analyzed the selection for treatment of patients at high risk of fracture by the Belgian FRISBEE imminent model and the FRAX® tool.Methods We identified in the FRISBEE cohort subjects who sustained an incident MOF (mean age 76.5 ± 6.8 years). We calculated their estimated 10-year risk of fracture using FRAX® before and after adjustment for recency and the 2-year probability of fracture using the FRISBEE model.ResultsAfter 6.8 years of follow-up, we validated 480 incident and 54 imminent MOFs. Of the subjects who had an imminent fracture, 94.0% had a fracture risk estimated above 20% by the FRAX® before correction for recency and 98.1% after adjustment, with a specificity of 20.2% and 5.9%, respectively. The sensitivity and specificity of the FRISBEE model at 2 years were 72.2% and 55.4%, respectively, for a threshold of 10%.For these thresholds, 47.3% of the patients were identified at high risk in both models before the correction, and 17.2% of them had an imminent MOF. The adjustment for recency did not change this selection. Before the correction, 34.2% of patients were selected for treatment by FRAX® only, and 18.8% would have had an imminent MOF. This percentage increased to 47% after the adjustment for recency, but only 6% of those would suffer a MOF within 2 years.Conclusion In our Belgian FRISBEE cohort, the imminent model was less sensitive but more selective in the selection of subjects in whom an imminent fracture should be prevented, resulting in a lower NNT. The correction for recency in this elderly population further decreased the selectivity of FRAX®. These data should be validated in additional cohorts before using them in everyday practice.

Introduction: Prediction models, especially the FRAX®, are largely used to estimate the fracture risk at ten years, but the current algorithm does not take into account the time elapsed after a fracture. Kanis et al. recently proposed correction factors allowing to adjust the FRAX® score for fracture recency. The objective of this work was to analyze the effect of fracture recency in the FRISBEE cohort. Methods: We identified in the FRISBEE cohort subjects who sustained a validated fracture during the first 5 years following an incident MOF. We calculated their estimated 5-year risk of fracture using FRAX® uncorrected, adjusted for recency and further adjusted for the MOF/hip ratios calibration factors previously derived for the Belgian FRAX®. We compared the fracture risk estimated by FRAX® before and after these corrections to the observed incidence of validated fractures in our cohort. Results: In our ongoing cohort, 376 subjects had a first non-traumatic incident validated MOF after inclusion; 81 had a secondary fracture during the 5 years follow-up period after this index fracture. The FRAX® score significantly under-evaluated the observed incidence of fractures in our cohort by 54.7 % (fracture rate of 9.7 %; 95 % CI, 6.8-12.9 %) if uncorrected (p < 0.001) and by 32.6 % after correction for recency (14.5 %; 95 % CI, 11.1-18.2 %) (p = 0.01). The calibration for MOF/hip ratios improved the prediction (17.5 %; 95 % CI: 13.7-21.4 %) (p = 0.2). After correcting for recency and for calibration, the predicted value was over-evaluated by 22 % (fracture rate of 26.1 %; 95 % CI, 21.6-30.5 %) but this over-evaluation was not significant (p = 0.1). Conclusion: Our data indicate that the correction of the FRAX® score for fracture recency improves fracture prediction. However, correction for calibration and recency tends to overestimate fracture risk in this population of elderly women.