Delphine Stoll

Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports

Osteoporosis treatments are usually given for a limited period of time in order to balance benefits and risks. We report three cases of postmenopausal women without any previous fragility fracture who presented severe spontaneous vertebral fractures after denosumab discontinuation. We think that the occurrence of these fractures could be explained by the severe rebound effect observed after denosumab discontinuation and that a consensus regarding the end of treatment with denosumab has to be defined.

Severe rebound-associated vertebral fractures after denosumab discontinuation: nine 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 prevalence of hypovitaminosis D in a Swiss rheumatology outpatient population.

Vitamin D is important for bone metabolism and neuromuscular function. While a routine dosage is often proposed in osteoporotic patients, it is not so evident in rheumatology outpatients where it has been shown that the prevalence of hypovitaminosis D is high. The aim of the current study was to systematically evaluate the vitamin D status in our outpatient rheumatology population to define the severity of the problem according to rheumatologic diseases. During November 2009, all patients were offered a screening test for 25-OH vitamin D levels and categorised as deficient (<10 µg/l [ng/ml] [25 nmol/l]), insufficient (10 µg/l to 30 µg/l [25 to 75 nmol/l]) or normal (>30 µg/l [75 nmol/l]). A total of 272 patients were included. The mean 25-OH vitamin D level was 21 µg/l (range 1.5 to 45.9). A total of 20 patients had vitamin D deficiency, 215 patients had an insufficiency and 37 patients had normal results. In the group of patients with osteoporosis mean level of 25-OH vitamin D was 25 µg/l and 31% had normal results. In patients with inflammatory rheumatic diseases (N = 219), the mean level of 25-OH vitamin D was 20.5 µg/l, and only 12% had normal 25-OH vitamin D levels. In the small group of patients with degenerative disease (N = 33), the mean level of 25-OH vitamin D was 21.8 µg/l, and 21% had normal results. Insufficiency and deficiency were even seen in 38% of the patients who were taking supplements. These results confirm that hypovitaminosis D is highly prevalent in an outpatient population of rheumatology patients, affecting 86% of subjects. Despite oral supplementation (taken in 38% of our population), only a quarter of those on oral supplementation attained normal values of 25-OH vitamin D.

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.

Changing the awareness of low vitamin D status in a rheumatology population: a pre/post-study

INTRODUCTION In 2009 hypovitaminosis D was highly prevalent in a population of Swiss rheumatology patients (86%). We aimed to evaluate the evolution of vitamin D status in the same population two years later, after the results of the first study were disseminated to local physicians and patients, in order to determine the evolution of the problem and the impact of physician information. METHOD Patients in our rheumatology clinic were screened for 25-OH vitamin D. Results were categorised as: deficient (<10 ng/ml or <25 nmol/l), insufficient (10 to 30 ng/ml or 25 to 75 nmol/l) or normal (>30 ng/ml or >75 nmol/l). We also used another cut-off of 20 ng/ml (50 nmol/l). We evaluated the evolution of 25-OH vitamin D dosages and vitamin D3 prescriptions between 2008 and 2011 in our institution and the number of publications on vitamin D in three important medical journals of the French speaking part of Switzerland. RESULTS Compared with 2009, significantly more patients had normal results in 2011. Fifty-two percent of patients had levels >20 ng/ml in 2009 and 66% in 2011, difference statistically significant (p = 0.001). During the years separating the two study periods the number of 25-OH vitamin D dosages and the prescription of high doses of vitamin D3 increased in our hospital. In addition the number of publications on vitamin D increased between 2008 and 2011. CONCLUSION We concluded that lower prevalence in hypovitaminosis D is certainly related to better adherence to daily supplements, and to better information and awareness of the physicians about hypovitaminosis D.

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.

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.

THU0461 Rebound-Associated Vertebral Fractures after Denosumab Discontinuation: A Series of 8 Women with 35 Spontaneous Vertebral Fractures

Background Osteoporosis (OP) treatments are given for a limited period of time because of a risk/benefice balance. Reversibility of OP treatment is observed by the measurements of bone markers turnover (BMTs) and bone mineral density (BMD). The effect on vertebral fracture (VFx) is difficult to evaluate. The OP treatment discontinuation is associated with an increase of BMTs and a more or less rapid decrease of BMD. Denosumab (Dmab) discontinuation is associated with a severe rebound effect on BTMs and BMD for near 24 months. A recent publication suggests an increase of VFx [1]. Methods We report the cases of 8 postmenopausal women. They received Dmab 60mg every 6 months for 2 to 8 doses. The 8 women were on calcium and vitamin D. A wide biological assessment excluded a secondary cause of OP. VFx were documented by MRI. Results Five OP women without any prior fragility fracture were treated every 6 months with 4 to 6 Dmab doses. Dmab was stopped because there was no more OP on BMD (3 women 55, 56 and 59 y old), the aromatase inhibitors were stopped (77y old) and according to the wish of the patient (77y old). 9 to 16 months after Dmab discontinuation, they presented respectively 5 (D11, D12, L2-L4), 7 (D9, D12-L5), 2 (D11 and D12), 3 (D12-L2) and 9 (D5-D9 and D11-L2) symptomatic spontaneous (SS) VFx. A 65 y old woman with osteoporosis and 3 prevalent VFx was treated every 6 months with 8 Dmab doses. Ten months after Dmab discontinuation she presented 2 SSVFx (D12, L3). These 62 y old woman (osteopenia, treated with aromatase inhibitors) received 2 Dmab doses every 6 months. The subsequent Dmab dose was forgotten. Twelve months after the last Dmab dose she presented a D10 SSFx. A 71 y old woman (one prevalent VFx and one hip fracture) received 2 Dmab doses with a delay of 11 months because of a lack of compliance. Eleven months after the last Dmab dose she presented 5 SSVFx (D12, L2-L5). Conclusions These 8 cases show a severe increased risk of vertebral fractures in the 9 to 16 months after the last injection of Dmab. The occurrence of these fractures can be explained by the severe rebound effect observed after denosumab discontinuation. It is urgent to: 1) inform the health authorities and patients of this risk; 2) determine treatment regimens before or at the time of denosumab discontinuation. References Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe vertebral fractures after denosumab discontinuation: 3 cases reports. Osteoporos Int. 2015 Oct 28. Disclosure of Interest None declared

Fractures atypiques du fémur: A propos de trois cas cliniques

Osteoporosis is an increasing public health problem. The bisphophonates are the most useful treatment used through the world to prevent osteoporotic fractures. Their large prescription revealed an unpredictable side effect: the atypical fracture. These fractures appear in the subtrochanteric or diaphysal femoral proximal site, spontaneously or after a low trauma, and could be bilateral. X-rays shows a transversal or oblique fracture with a spur in the cortex and with a diffuse thickening of the cortical of the proximal femur. Experts recommendations are current in progress to well understand and managed this problem. Here we report three cases of atypical femur fractures occurred in our Centre of bone diseases with some management and treatment propositions.