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.

Stopping Denosumab.

PURPOSE OF REVIEW: Denosumab discontinuation is associated with a rebound effect manifesting by an increased risk of multiple spontaneous vertebral fractures. The purpose of this review is to (1) better characterize this risk and (2) find solutions to avoid it. RECENT FINDINGS: In the absence of a potent bisphosphonate prescription at denosumab discontinuation, the frequency of multiple vertebral fractures is common or frequent (≥ 1/100 and < 1/10). In five recent case series, the median number of vertebral fractures was 5 within 7 to 20 months (median 11) after the last denosumab injection. Prescribing bisphosphonate before starting denosumab and/or after stopping denosumab may reduce this risk. However, only small case series have evaluated these strategies. After the second denosumab dose, there is a rebound effect with an increased risk of multiple vertebral fractures. A potent bisphosphonate prescribed at denosumab discontinuation could reduce this risk. As denosumab discontinuation is characterized by many uncertainties, denosumab is a second-line treatment for osteoporosis. Studies are urgently needed to define the management of denosumab discontinuation.

[What can we do at the discovery of an osteroporotic vertebral fracture†?] / Que faire face à une fracture vertébrale ostéoporotique†?

Osteoporotic vertebral fractures (VF) are common and can induce acute and chronic pain, having a negative impact on quality of life and lifespan. One man and one women over five will have one or more osteoporotic VF after the age of 50. The screening of these fractures is important because they are predictive of subsequent fractures. Most of the vertebral fractures are asymptomatic and therefore under-diagnosed. Clinics is the first screening tool and radiologic imaging will confirm any suspicion. The initiation of anti-fracture treatment is crucial to avoid future fractures. Physiotherapy and analgesics are part of the management of pain as well as vertebroplasty or kyphoplasty.

Les fractures vertébrales (FV) ostéoporotiques sont fréquentes et sont à l'origine de douleurs aiguës et chroniques ayant un impact important sur la qualité et la durée de vie. Un homme et une femme sur cinq présenteront une ou plusieurs FV ostéoporotiques après l'âge de 50 ans. Le dépistage de ces fractures est important car elles sont fortement prédictives de fractures subséquentes. La majorité des FV (> 60 %) sont asymptomatiques donc sous-diagnostiquées. L'examen clinique est le premier outil de dépistage des FV et les différentes imageries permettront de confirmer le diagnostic. L'initiation d'un traitement anti-fracturaire est primordiale afin d'éviter de futures fractures. La physiothérapie et les traitements antalgiques aideront à la gestion de la douleur, parfois renforcée par la vertébroplastie ou la kyphoplastie.

[How to manage the rebound effect at denosumab discontinuation and avoid multiple vertebral fractures?] / Comment gérer l'effet rebond à l'arrêt du dénosumab et éviter les fractures vertébrales multiples†?

Denosumab discontinuation is associated with a severe rebound effect combining elevation of bone remodeling markers for two years and loss of the gained bone density. In the absence of a potent bisphosphonate prescription at denosumab discontinuation, multiple vertebral fractures are frequent. The median number of vertebral fractures is 5, within 7 to 20 months (median 11) after the last denosumab injection. A potent bisphosphonate prescribed at denosumab discontinuation may reduce this risk. This strategy requires close monitoring of bone remodeling markers and adjustment of treatment if bone remodeling is not controlled.

L'arrêt du dénosumab est associé à un effet rebond sévère associant élévation des marqueurs du remodelage osseux pour deux ans et perte du gain de densité osseuse. A l'arrêt du dénosumab, en l'absence de prescription d'un puissant bisphosphonate, la fréquence des fractures vertébrales multiples est élevée. Le nombre médian de fractures vertébrales est de 5 dans les 7 à 20 mois (médiane 11) suivant la dernière injection de dénosumab. Un bisphosphonate puissant prescrit à l'arrêt du traitement de dénosumab pourrait réduire ce risque. Cette stratégie nécessite un suivi serré des marqueurs du remodelage osseux et un ajustement du traitement si le remodelage osseux n'est pas suffisamment contrôlé.

[Phosphocalcic anomalies and bone fragility keys for the general practitioner]. / Bilan phosphocalcique perturbé dans le cadre d'une fragilité osseuse : des clés pour le praticien.

How to recognize secondary causes of bone fragility in relation with an abnormal calcium and phosphate laboratory in general practice ? Through clinical cases presentations we will discuss the calcium and phosphate abnormalities which can be related to bone fragility and for which a-specific approach must be proposed. It can be abnormal results of calcium, phosphate or vitamin D. Some causes are frequent, others are iatrogenic, and others are related to a rare disease sometimes of genetic cause which consequences are more important than expected.

Comment reconnaître les causes secondaires de fragilité osseuse liées à un bilan phosphocalcique perturbé au cabinet ? A travers des vignettes cliniques, nous aborderons les désordres phosphocalciques qui peuvent être à l'origine d'une fragilité osseuse et pour lesquels une prise en charge indépendante doit être proposée. Il peut s'agir de la découverte d'une anomalie du calcium, du phosphate ou de la vitamine D. Certaines causes sont fréquentes, d'autres iatrogènes, et d'autres débouchent sur le diagnostic d'une maladie rare parfois de cause génétique dont les conséquences sont plus importantes que prévu.

[Denosumab in clinical practice : beware before, during and after]. / Dénosumab en routine clinique: précautions à prendre avant, pendant et après.

Denosumab is a very effective treatment of osteoporosis, easy to use and very well tolerated. Due to some associated risks, a close clinical follow-up is necessary. Before the first injection, it is necessary to correct hypocalcaemia or vitamin D deficiency when present. Calcemia has to be followed in case of renal insufficiency. Injections of denosumab should be done scrupulously every 6 months (± 3 weeks). Discontinuation of denosumab is associated with a severe rebound effect characterized by increased markers of bone remodeling, a rapid decrease of bone density values, and a risk of multiple spontaneous vertebral fractures. The administration of a potent bisphosphonate (zoledronate, alendronate) minimises or avoids this rebound effect.

Le dénosumab est un traitement très efficace de l'ostéoporose, simple d'utilisation et très bien toléré. Au vu de certains risques associés, un suivi clinique rapproché est nécessaire. Lors de son initiation, il faut corriger une hypocalcémie ou un déficit en vitamine D. Il faut suivre la calcémie en présence d'une insuffisance rénale. Les injections de dénosumab sont à faire scrupuleusement tous les 6 mois (± 3 semaines). L'arrêt du dénosumab s'accompagne d'un effet rebond sévère, caractérisé par une augmentation des marqueurs du remodelage osseux, une diminution rapide des valeurs de densité osseuse et un risque de fractures vertébrales multiples spontanées. L'administration d'un bisphosphonate puissant (zolédronate, alendronate) permet de pallier cet effet rebond.

[Testosterone and bone: indications and limitations]. / Testostérone et os: indications et limites.

Osteoporosis incidence increases exponentially with age in men and hypogonadism represents a risk factor. Sex steroids levels are correlated to bone mineral density and to fracture prevalence. Most studies demonstrate an improvement in bone mineral density in men with hypogonadism as a result of testosterone therapy. Nevertheless there are no data evaluating the effect of testosterone therapy on fractures in men. Approximately 20% of men older than 60 have a total testosterone level lower than the lower limit of the reference range but there is no true consensus on the definition of hypogonadism in older men. In older men we recommend to treat only if total morning testosterone levels are < 8 nmol/l or even < 6,9 nmol/l on several occasions in the absence of any reversible illness and if there is no contraindication for treatment.

Clinical Performance of the Updated Trabecular Bone Score (TBS) Algorithm, Which Accounts for the Soft Tissue Thickness: The OsteoLaus Study.

Regional soft tissue may have a noise effect on trabecular bone score (TBS) and eventually alter its estimate. The current TBS software (TBS iNsight®) is based on an algorithm accounting for body mass index (BMI) (TBSv3.03 ). We aimed to explore the updated TBS algorithm that accounts for soft tissue thickness (TBSv4.0 ). This study was embedded in the OsteoLaus cohort of women in Lausanne, Switzerland. Hip and lumbar spine (LS) dual-energy X-ray absorptiometry (DXA) scans were performed using Discovery A System (Hologic). The incident major osteoporotic fractures (MOFs) were assessed from vertebral fracture assessments using Genant's method (vertebral MOF) or questionnaires (nonvertebral MOF). We assessed the correlations of bone mineral density (BMD) or TBS with body composition parameters; MOF prediction ability of both versions of TBS; and the differences between Fracture Risk Assessment Tool (FRAX) adjusted for TBSv3.03 or TBSv4.0 . In total, 1362 women with mean ± SD age 64.4 ± 7.5 years and mean ± SD BMI 25.9 ± 4.5 kg/m2 were followed for 4.4 years and 132 experienced an MOF. All the anthropometric measurements of our interest were positively correlated with LS, femoral neck, or hip BMD and TBSv4.0 ; whereas with TBSv3.03 their correlations were negative. In the models adjusted for age, soft tissue thickness, osteoporotic treatment, and LS-BMD, for each SD decline in TBSv3.03 , there was a 43% (OR 1.43; 95% CI, 1.12 to 1.83) increase in the odds of having MOF; whereas for each SD decline in TBSv4.0 , there was a 54% (OR 1.54; 95% CI, 1.18 to 2.00) increase in the odds of having an MOF. Both FRAXs were very strongly correlated and the mild differences were present in the already high-risk women for MOF. This study shows that TBSv4.0 overcomes the debatable residual negative correlation of the current TBS with body size and composition parameters, postulating itself as free from the previously acknowledged technical limitation of TBS. © 2019 American Society for Bone and Mineral Research.

Raloxifene Has No Efficacy in Reducing the High Bone Turnover and the Risk of Spontaneous Vertebral Fractures after Denosumab Discontinuation.

At denosumab discontinuation, an antiresorptive agent is prescribed to reduce the high bone turnover, the rapid bone loss, and the risk of spontaneous vertebral fractures. We report the case of a woman treated with aromatase inhibitors and denosumab for 5 years. Raloxifene was then prescribed to prevent the rebound effect. Raloxifene was ineffective to reduce the high bone turnover and to avoid spontaneous clinical vertebral fractures. We believe that among the antiresorptive treatments, the most powerful bisphosphonates should be favored, and their administration adapted according to the serial follow-up of bone markers.

[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.

Impact of a fracture liaison service on patient management after an osteoporotic fracture: the CHUV FLS.

In 2008, the Centre Hospitalier Universitaire Vaudois (CHUV, Lausanne, Switzerland) initiated a Fracture Liaison Service (FLS). All patients hospitalised for a low trauma fracture are identified by the FLS. Inpatients then choose to be managed by either the FLS team or their general practitioner (GP). In this study we compared the management between the FLS team and the GP in terms of diagnosis of osteoporosis, treatment, refracture rates and mortality after FLS recording. Results are compared with the management of osteoporosis before the creation of the FLS, as reported in the survey study Osteocare. A total of 606 patients were included (80% women); 55% chose management by the FLS and 45% their GP. The mean age was 78.5, and hip was the main fracture site (44%). The percentage of patients having dual X-ray absorptiometry to diagnose osteoporosis was significantly higher in the FLS group than the GP group (72 vs 26.5%, p <0.01). This percentage was 31.4% in the Osteocare study. Overall, 50.3% of patients in the FLS group had osteoporosis versus 57.5% in the GP group (p <0.05). This percentage was 46.0% in the Osteocare study. Use of osteoporosis medication was higher in the FLS group (FLS 100% of the patients, GP 44.1%, p <0.001) and had increased since the Osteocare study (21.6%). One-year nonvertebral refracture rate was higher in GP group than in the FLS patients (5.1 vs 3.0%, p <0.05), whereas more vertebral fractures were identified in the FLS group, owing to protocol-driven regular clinical and vertebral fracture assessment (VFA) evaluations (number of evaluations 8 vs 0, p <0.01). Unadjusted mortality was higher in GP group than in the FLS group at one and five years (6.93 vs 2.11% and 33.58 vs. 15.96%, p <0.04). After adjustment by age and fracture site, these results were not significant. With FLS management, diagnosis and treatment of osteoporosis were more frequent than with GP management; new nonvertebral fractures were less frequent. Moreover, both forms of management had increased relative to rates reported in a 2004-2006 nationwide survey Osteocare, before FLS creation.

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.

High Evening Cortisol Level Is Associated With Low TBS and Increased Prevalent Vertebral Fractures: OsteoLaus Study.

Context: Increased evening cortisol levels have been implicated in bone mineral density (BMD) loss. The effect on bone microarchitecture and fracture risk has never been studied. Objective: To study the relationship between salivary cortisol circadian rhythm and (1) trabecular bone score (TBS) and (2) fracture prevalence. Design, Setting, Patients, and Interventions: Cross-sectional study including 608 women >50 years old (mean = 65.5) from the OsteoLaus cohort. Data included the FRAX© questionnaire, BMD, TBS and vertebral fracture (VFx) assessment by dual X-ray absorptiometry, and measures of salivary cortisol (awakening, 30 minutes thereafter, 11 am, and 8 pm). Results: In the multivariate model, participants in the highest tertile of 8 pm salivary cortisol (sc-8 pm) (mean = 5.7 ± 2.5 nmol/L) vs lowest tertile (1.7 ± 0.4 nmol/L) had lower TBS values (1.27 vs 1.29; P = 0.02), more prevalent VFx grades 2 and 3 (odds ratio = 5.34; P = 0.012), low-trauma fractures (odds ratio = 1.80; P = 0.036), and major osteoporotic fractures (odds ratio = 1.96; P = 0.042), without difference in lumbar spine BMD (0.91 vs 0.92 g/cm2; P = 0.431). VFx prevalence was associated with sc-8 pm and TBS independently of each other and of other risk factors. The cut-point for sc-8 pm correlating with the presence of >1 VFx was 3.62 nmol/L (sensitivity 0.74, specificity 0.66). Conclusions: High sc-8 pm is associated with low TBS and an increased prevalence of radiologic VFx independently of other risk factors. Measurement of sc-8 pm may add relevant information in the assessment of fracture risk.

Short-term administration of isotretinoin elevates plasma triglyceride concentrations without affecting insulin sensitivity in healthy humans.

The mechanism underlying hypertriglyceridemia-associated insulin resistance in humans remains poorly understood. It has been proposed that hypertriglyceridemia only produces insulin resistance when associated with an increased lipid delivery to muscle. Accordingly, hypertriglyceridemia secondary to a decreased clearance of triglyceride-rich particles should not cause insulin resistance. To verify this hypothesis, we assessed whole body and adipose tissue insulin sensitivity in 15 healthy male volunteers before and after a 5-day administration of isotretinoin (1 mg/kg/d), a vitamin A derivative that decreases the clearance of triglyceride-rich particles. Whole body insulin-mediated glucose disposal (6,6 (2)H(2)glucose), glucose oxidation (indirect calorimetry), lipolysis ((2)H(5) glycerol), and subcutaneous adipose lipolysis (microdialysis) were evaluated during a 3-step hyperinsulinemic euglycemic clamp. Isotretinoin increased plasma triglyceride from 0.97 +/- 0.15 to 1.30 +/- 0.22 mmol/L (P <.02), but did not change whole body insulin-mediated glucose disposal and lipolysis. These observations are consistent with an isotretinoin-induced inhibition of very-low-density lipoprotein (VLDL)-triglyceride clearance. The suppression of endogenous glucose production and the reduction in subcutaneous adipose glycerol concentrations by insulin remained equally unaffected after isotretinoin administration. We conclude that the impaired clearance of triglyceride-rich particles secondary to a 5-day isotretinoin administration does not impair insulin-mediated antilipolysis or glucose disposal. The data support the concept that hypertriglyceridemia-associated insulin resistance develops primarily when triglyceride production is increased.