Postmenopausal women with normal BMD who have fractures have deteriorated bone microarchitecture: A prospective analysis from The OFELY study.

Most postmenopausal women who sustain fragility fracture (Fx) have their areal bone mineral density (BMD) above the osteoporosis threshold. A sizeable proportion of them have normal aBMD. This study aimed to prospectively investigate the association of fragility Fx with bone microarchitecture (MA) assessed by high-resolution peripheral computed tomography (HR-pQCT) in postmenopausal women without low BMD. At the 14th annual follow-up of the OFELY study, we measured bone MA at the distal radius and tibia with HR-pQCT in addition to areal BMD with DXA, in 586 postmenopausal women. Among them, 166 (29 %) women, mean (SD) age 65 (8) yr, had normal BMD defined as a T score ≥ -1 at the lumbar spine, femoral neck, and total hip. During a median [IQR] 15 [14-15] yr of follow-up, 46 of those women sustained incident fragility Fx, including 19 women with a major osteoporotic Fx (clinical spine, forearm, proximal humerus, hip). Women who sustained Fx did not differ for age, BMI, tobacco and alcohol use, diabetes, falls, FRAX®, aBMD, and TBS compared with women without incident Fx. In contrast, they had significant impairment of volumetric densities, cortical area (Ct. Ar) and thickness (Ct. Th), stiffness (K), and estimated failure load (FL) at the radius compared with women without incident Fx. At the radius, each SD decrease of volumetric densities, Ct.Ar, Ct.Th, K, and estimated FL were significantly associated with an increased risk of all fragility fractures with hazard ratios (HR) from 1.44 to 1.56 and of major osteoporotic fractures (HR from 1.66 to 2.57). Lesser impairment of bone MA was seen at the tibia. We conclude that even in women with normal areal BMD fragility fractures are associated with deterioration of bone microarchitecture.

Pre-treatment bone turnover does not influence the level of the response to alendronate in postmenopausal osteoporosis at the bone tissue level.

PURPOSE: The main effect of anti-resorptive agents such as bisphosphonates is a reduction of bone resorption, with a consequent marked decrease of bone turnover. This post-hoc analysis investigated the changes of histomorphometric parameters of bone turnover after alendronate (ALN), according to the baseline turnover. METHODS: Ninety postmenopausal women underwent a transiliac bone biopsy before and after 6 (n = 44) or 12 (n = 46) months of treatment with ALN (70 mg/week). The dynamic parameters reflecting the bone formation and bone turnover were mineralizing surface (MS/BS; %), bone formation rate (BFR/BS; µm3/µm2/d), and activation frequency (Ac.f; /yr). Biochemical markers sPINP and the sCTX were assessed before treatment and after 3, 6, and 12 months. Subjects were divided into quartiles based on the baseline values of BFR/BS. RESULTS: At baseline, MS/BS and Ac.f were significantly different (p < 0.0001) among the BFR quartiles. sCTX and sP1NP were not significantly different among quartiles. After ALN treatment, MS/BS was not significantly different among quartiles but Ac.f remained significantly lower in the first quartile compared to the third and fourth ones (p < 0.03). The absolute value of the difference between pre- and post-treatment significantly correlated with the baseline BFR/BS but when expressed in percent of the baseline value, the magnitude of the diminutions of MS/BS, Ac.f, sCTX, and sP1NP was similar in the four baseline BFR quartiles. CONCLUSION: The percentage response to ALN appeared independent of the baseline level of bone turnover. After treatment, the bone turnover tended to be similar in all BFR quartiles. This analysis investigated the influence of baseline turnover measured by bone histomorphometry on the effect of alendronate. When expressed in percent of pre-treatment values, the decreases of histomorphometric parameters and biochemical markers of bone turnover were independent of the baseline turnover.

Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone.

INTRODUCTION: Reference Centers and Rare Disease Health Networks aim to improve the management of patients with rare diseases. The French reference center for Fibrous Dysplasia was certified in 2006. OBJECTIVE: The objective of our study was to assess the effectiveness of our reference center since its constitution. METHODS: In a retrospective cohort study, we compared the activity of our center, including the time elapsed between access to the center and the diagnostic delay of patients with Fibrous Dysplasia between two periods, 1994-2006 (before certification) and 2007-2019 (after certification). Data were extracted from patients' records (Easily®). Wilcoxon and Fisher tests were performed, using R®. RESULTS: Our cohort included 527 patients with Fibrous Dysplasia/Mc Cune Albright syndrome. The activity of the Fibrous Dysplasia center increased from 139 patients in the first period (1994-2006) to an additional 388 patients for the second period (2007-2019). Mean time elapsed to diagnosis of Fibrous Dysplasia was 1.5 years before 2007 and 1.9 years after 2007 (p = 0.12). Diagnosis was made before referral in over 80% of patients. There was a non-significant decrease in the number of patients with delayed diagnosis: 37 patients (44%) in the first period had a diagnostic delay and 94 patients (33%) in the second period (p = 0.07). Patients were referred to our center on average 6.8 years (before 2007) and 7.9 years (after 2007) after their diagnosis (p = 0.77). CONCLUSION: Healthcare organization with reference centers significantly impacted the management of patients with Fibrous Dysplasia/Mc Cune Albright syndrome, with a substantial increase in the activity of our center, that roughly tripled since certification. This healthcare organization was also associated with a trend toward decreasing diagnostic delay. However, diagnostic delay affected more than a third of patients and the time to access to the center remained extended (≈7-8 years after diagnosis). The current challenge lies in informing primary care providers and patients about education to rare diseases and existence of reference centers for earlier and more effective specialized management.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study.

INTRODUCTION: Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. MATERIALS AND METHODS: We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). RESULTS: 13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DISCUSSION: This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. CONCLUSION: Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Murine models of posterolateral spinal fusion: A systematic review.

BACKGROUND: Rodent models are commonly used experimentally to assess treatment effectiveness in spinal fusion. Certain factors are associated with better fusion rates. The objectives of the present study were to report the protocols most frequently used, to evaluate factors known to positively influence fusion rate, and to identify new factors. METHOD: A systematic literature search of PubMed and Web of Science found 139 experimental studies of posterolateral lumbar spinal fusion in rodent models. Data for level and location of fusion, animal strain, sex, weight and age, graft, decortication, fusion assessment and fusion and mortality rates were collected and analyzed. RESULTS: The standard murine model for spinal fusion was male Sprague Dawley rats of 295g weight and 13 weeks' age, using decortication, with L4-L5 as fusion level. The last two criteria were associated with significantly better fusion rates. On manual palpation, the overall mean fusion rate in rats was 58% and the autograft mean fusion rate was 61%. Most studies evaluated fusion as a binary on manual palpation, and only a few used CT and histology. Average mortality was 3.03% in rats and 1.56% in mice. CONCLUSIONS: These results suggest using a rat model, younger than 10 weeks and weighing more than 300 grams on the day of surgery, to optimize fusion rates, with decortication before grafting and fusing the L4-L5 level.

The disability associated with hand osteoarthritis is substantial in a cohort of post-menopausal women: the QUALYOR study.

OBJECTIVES: Our primary aims were to assess current prevalence of HOA and the disability associated with this condition, in the group usually most affected, i.e., women older than 55. METHODS: We performed hand radiographs, clinical examination, grip strength measurement, AUSCAN and COCHIN questionnaires in a cohort of postmenopausal women aged at least 55. Radiographic hand OA (RHOA) was defined as at least 2 affected joints among 30, grading 2 or more using the Kellgren Lawrence score but without any HOA symptom. Symptomatic HOA (OA ACR) was defined according to ACR criteria for hand OA. Moderate to severe symptomatic HOA was defined as having OA ACR and AUSCAN total score of >43/100. RESULTS: We enrolled 1,189 participants. The mean age was 71.7 years. Inter-reader reliability of radiographs reading was good (ICC = 0.86) and intra-reader reliability was excellent (ICC = 0.97). Among the 1,189 women, 333 (28.0%) had RHOA, 482 (40.5%) patients fulfilled the ACR criteria for symptomatic HOA and 82 of these (17% of OA ACR population) had moderate to severe symptomatic HOA. The prevalence of symptomatic erosive osteoarthritis was 11.8%. Mean AUSCAN and Cochin scores were higher and grip strength lower in patients with symptomatic HOA compared to patient without HOA. Differences were more noticeable in patients with moderate to severe HOA. CONCLUSIONS: We have assessed disability associated with HOA in greater detail than previously and found that a third of postmenopausal women had RHOA, two fifths had symptomatic HOA and one sixth of symptomatic patients had moderate to severe HOA related disability and a tenth had symptomatic erosive osteoarthritis, representing a substantial burden of disease in our population-based cohort.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Klinefelter Bone Microarchitecture Evolution with Testosterone Replacement Therapy.

Klinefelter Syndrome (KS) patients, defined by a 47 XXY karyotype, have increased risk of fragility fractures. We have assessed bone microarchitecture by high resolution peripheral quantitative CT (HR-pQCT) at the radius and tibia in young KS patients, naïve from testosterone replacement therapy (TRT). Areal bone mineral density (BMD) and body composition were assessed by dual X-ray absorptiometry (DXA). Total testosterone (tT) was measured at baseline. Bone measurements have been repeated after 30 months of TRT. We enrolled 24 KS patients and 72 age-matched controls. KS patients were (mean ± SD) 23.7 ± 7.8 year-old. KS patients had significantly lower relative appendicular lean mass index (RALM) and lower aBMD at spine and hip than controls. Ten patients (42%) had low tT level (≤ 10.4 nmol/L). At baseline, we observed at radius a marked cortical (Ct) impairment reflected by lower Ct.area, Ct.perimeter, and Ct.vBMD than controls. At tibia, in addition to cortical fragility, we also found significant alterations of trabecular (Tb) compartment with lower trabecular bone volume (BV/TV) and Tb.vBMD as compared to controls. After 30 months of TRT, 18 (75%) KS patients were reassessed. Spine aBMD and RALM significantly increased. At radius, both cortical (Ct.Pm, Ct.Ar, Ct.vBMD, Ct.Th) and trabecular (Tb.vBMD) parameters significantly improved. At tibia, the improvement was found only in the cortical compartment. Young TRT naïve KS patients have inadequate bone microarchitecture at both the radius and tibia, which can improve on TRT.

The global approach to rehabilitation following an osteoporotic fragility fracture: A review of the rehabilitation working group of the International Osteoporosis Foundation (IOF) committee of scientific advisors.

PURPOSE: To conduct a review of the current state of the evidence for rehabilitation strategies post-fragility fracture. METHODS: Narrative review conducted by the Rehabilitation Working Group of the International Osteoporosis Foundation Committee of Scientific Advisors characterizing the range of rehabilitation modalities instrumental for the management of fragility fractures. RESULTS: Multi-modal exercise post-fragility fracture to the spine and hip is strongly recommended to reduce pain, improve physical function, and improve quality of life. Outpatient physiotherapy post-hip fracture has a stronger evidence base than outpatient physiotherapy post-vertebral fracture. Appropriate nutritional care after fragility fracture provides a large range of improvement in morbidity and mortality. Education increases understanding of osteoporosis which in turn increases utilization of other rehabilitation services. Education may improve other health outcomes such as pain and increase a patient's ability for self-advocacy. CONCLUSION: Rehabilitation interventions are inter-reliant, and research investigating the interaction of exercise, nutrition, and other multi-modal therapies may increase the relevance of rehabilitation research to clinical care.

Reference microarchitectural values measured by HR-pQCT in a Franco-Swiss cohort of young adult women.

Bone microarchitecture assessed by high-resolution peripheral quantitative computed tomography varies across populations of different origin. The study presents a reference dataset of microarchitectural parameters in a homogeneous group of participants aged within 22-27 range determined by a discriminant analysis of a larger cross-sectional cohort of 339 women. INTRODUCTION: High-resolution peripheral quantitative computed tomography (HR-pQCT) non-invasively measures three-dimensional bone microarchitectural parameters and volumetric bone mineral density. Previous studies established normative reference HR-pQCT datasets for several populations, but there were few data assessed in a reference group of young women with Caucasian ethnicity living in Western Europe. It is important to obtain different specific reference dataset for a valid interpretation of cortical and trabecular microarchitecture data. The aim of our study was to find the population with the most optimal bone status in order to establish a descriptive reference HR-pQCT dataset in a young and healthy normal-weight female cohort living in a European area including Geneva, Switzerland, Lyon and Saint-Etienne, France. METHODS: We constituted a cross-sectional cohort of 339 women aged 19-41 years with a BMI > 18 and < 30 kg/m2. All participants had HR-pQCT measurements at both non-dominant distal radius and tibia sites. RESULTS: We observed that microarchitectural parameters begin to decline before the age of 30 years. Based on a discriminant analysis, the optimal bone profile in this population was observed between the age range of 22 to 27 years. Consequently, we considered 43 participants aged 22-27 years to establish a reference dataset with median values and percentiles. CONCLUSION: This is the first study providing reference values of HR-pQCT measurements considering specific age bounds in a Franco-Swiss female cohort at the distal radius and tibia sites.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Rapid Progression of Aortic Calcification in Older Men with Low Appendicular Lean Mass and Poor Physical Function.

OBJECTIVES: Assessment of the progression of abdominal aortic calcification (AAC) may be a surrogate marker of the impact of physical function on cardiovascular risk. Our aim was to assess the risk of rapid AAC progression in older men with low relative appendicular lean mass (RALM) and poor physical function. DESIGN: Prospective cohort study. SETTING: Community-dwelling older men. PARTICIPANTS: 621 men aged 50-85 followed prospectively (baseline, 3 and 7.5 years). MEASUREMENTS: Body composition was assessed by DXA. Poor physical function was defined as incapacity to perform ≥1 of 5 clinical tests (balance, muscle strength). AAC was assessed using Kauppila's semiquantitative score. Reclassification improvement was assessed by comparing the areas under the curve (AUC) using DeLong's method. RESULTS: Rapid AAC progression (>0.6 point/year) was found in 168 men (27.1%). After adjustment for confounders including baseline AAC, the risk of rapid AAC progression increased with lower RALM (OR=1.42/SD, 95%CI: 1.09-1.86, p<0.01) and was higher in the lowest (<7.5kg/m2) vs. highest (>8.6kg/m2) quartile (OR=2.15, 95%CI: 1.17-3.95, p<0.01). Poor physical performance was associated with rapid AAC progression (OR=2.76, 95%CI: 1.48-5.91, p<0.005). Low RALM (<7.84kg/m2 defined using Youden's index) and poor physical function contributed to the risk of rapid AAC progression jointly. Men who had low RALM and poor physical function had higher risk of rapid AAC progression vs. men without these traits (OR=4.66, 95%CI: 1.72-12.62, p<0.05). RALM and physical function improved the identification of men with rapid AAC progression (DAUC=0.026, 95%CI: 0.005-0.046, p<0.05) after adjustment for confounders including baseline AAC score. CONCLUSIONS: Low RALM and poor physical function are associated with higher risk of rapid AAC progression and possibly represent another measure of cardiovascular risk.

The clinical application of high-resolution peripheral computed tomography (HR-pQCT) in adults: state of the art and future directions.

High-resolution peripheral computed tomography (HR-pQCT) was developed to image bone microarchitecture in vivo at peripheral skeletal sites. Since the introduction of HR-pQCT in 2005, clinical research to gain insight into pathophysiology of skeletal fragility and to improve prediction of fractures has grown. Meanwhile, the second-generation HR-pQCT device has been introduced, allowing novel applications such as hand joint imaging, assessment of subchondral bone and cartilage thickness in the knee, and distal radius fracture healing. This article provides an overview of the current clinical applications and guidance on interpretation of results, as well as future directions. Specifically, we provide an overview of (1) the differences and reference data for HR-pQCT variables by age, sex, and race/ethnicity; (2) fracture risk prediction using HR-pQCT; (3) the ability to monitor response of anti-osteoporosis therapy with HR-pQCT; (4) the use of HR-pQCT in patients with metabolic bone disorders and diseases leading to secondary osteoporosis; and (5) novel applications of HR-pQCT imaging. Finally, we summarize the status of the application of HR-pQCT in clinical practice and discuss future directions. From the clinical perspective, there are both challenges and opportunities for more widespread use of HR-pQCT. Assessment of bone microarchitecture by HR-pQCT improves fracture prediction in mostly normal or osteopenic elderly subjects beyond DXA of the hip, but the added value is marginal. The prospects of HR-pQCT in clinical practice need further study with respect to medication effects, metabolic bone disorders, rare bone diseases, and other applications such as hand joint imaging and fracture healing. The mostly unexplored potential may be the differentiation of patients with only moderately low BMD but severe microstructural deterioration, which would have important implications for the decision on therapeutical interventions.

Discriminating value of HR-pQCT for fractures in women with similar FRAX scores: A substudy of the FRISBEE cohort.

Areal bone mineral density (aBMD) has a low sensitivity to identify women at high fracture risk. The FRAX algorithm, by combining several clinical risk factors, might improve fracture prediction compared to aBMD alone. Several micro-architectural and biomechanical parameters which can be measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) are associated with fracture risk. HR-pQCT in combination or not with finite element analysis (FEA) may be used to improve bone strength prediction. Our aim was to assess whether HR-pQCT measurements (densities, cortical and trabecular microarchitecture, biomechanical proprieties assessed by FEA) had an added value in predicting fractures in a subgroup of women belonging to the Belgian FRISBEE cohort. One hundred nineteen women who sustained a fracture (aged 60 to 85 years) during the initial follow-up of our cohort had a radius and tibia examination by HR-pQCT and were compared with controls matched for their FRAX score at baseline. We found that low distal radius total (OR = 1.41 [1.07-1.86] per SD, p < 0.05) and trabecular densities (OR = 1.45 [1.10-1.90], p < 0.01), trabecular number (OR = 1.32 [1.01-1.72], p < 0.05), intra individual distribution of separation (OR = 0.73 [0.54-0.99], p < 0.05) as several FEA parameters were significantly associated with fractures. At the distal tibia, impaired cortical density (OR = 1.32 [1.03-1.70] per SD, p < 0.05) and thickness (OR = 1.29 [1.01-1.63], p < 0.05) and apparent modulus (OR = 1.30 [1.01-1.66], p < 0.05) were significantly correlated with fractures. A low ultra distal radial aBMD (UDR) measured at the time of HR-pQCT was significantly associated with fractures (OR = 1.67 [1.22-2.28], p < 0.01). Women from both groups were followed further after the realization of the HR-pQCT and 46 new fractures were registered. In this second part of the study, low UDR aBMD (OR = 1.66 [1.18-2.35], p < 0.01), total (OR = 1.48 [1.08-2.03], p < 0.05), cortical (OR = 1.40 [1.04-1.87], p < 0.05) and trabecular (OR = 1.37 [1.01-1.85], p < 0.05) densities or apparent modulus (OR = 1.49 [1.07-2.05], p < 0.05) at the radius were associated with a significant increase of fracture risk. At the tibia, only the cortical density was significantly associated with the fracture risk (OR = 1.34 [1.02-2.76], p < 0.05). These results confirm the interest of HR-pQCT measurements for the evaluation of fracture risk, also in women matched for their baseline FRAX score. They also highlight that UDR aBMD contains pertinent information.

Cost-effectiveness of treatment of women aged 70 years and older with both osteopenia and microstructural deterioration.

OBJECTIVE: Treatment is usually withheld from women with osteopenia even though they are the source of over 70% of all women having fragility fractures. As microstructural deterioration increases fracture risk and zoledronate reduces it, we aimed to determine whether identifying and treating women with osteopenia and severe microstructural deterioration is cost-effective. We also compared the health economic outcomes of 'global' versus 'targeted' treatment using SFS of women aged ≥70 years with osteopenia. DESIGN: We assessed the cost-effectiveness from using a Markov model that simulated 10-year follow up of women with osteopenia. Decision analysis compared measurement of distal radial microstructure using high resolution peripheral computed tomography (at a cost of USD $210) to target women with severe microstructural deterioration for zoledronate treatment, compared to standard care defined as measurement of bone mineral density (BMD) with treatment recommended when femoral neck BMD T score is ≤-2.5 SD with or without a prevalent fracture. In the 'global' treatment approach, high resolution peripheral quantitative tomography (HRpQCT) was not undertaken. SETTING: US healthcare system. PARTICIPANTS: A hypothetical cohort of 1000 women aged ≥70 years with osteopenia and no previous fractures was studied. MEASURES: Fractures, deaths, years of life lived, quality-adjusted life years (QALYs) lived and costs. Data inputs were obtained from published sources. A 3% annual discount rate was applied to future health benefits and costs. RESULTS: Women in the standard care group incurred 327 fractures during 7341.0 years and 4914.2 QALYs lived. Women in the intervention group incurred 300 fractures (number needed to treat 37) during 7359.2 years and 4928.8 QALYs lived. Net costs were USD $4,862,669 and $4,952,004, respectively, equating to 18.1 years of life saved and 14.6 QALYs saved, and incremental cost-effectiveness ratios of $4992 per year of life saved and $6135 per QALY saved. These ratios are well within the threshold considered to be cost-effective. Sensitivity analyses indicated the results were robust. Relative to standard of care, 'global' and 'targeted' treatment respectively resulted in 0.0364 vs. 0.0181 years of life (YoLS) saved per person, and 0.0292 and 0.0146 QALYs saved per person. The net costs per person for the respective approaches were $US 359 and $US 89. The incremental cost-effectiveness ratios were $9864 per YoLS and $12,290 per QALY saved for the 'global' approach and $4992 per YoLS and $6135 per QALY saved for the 'targeted' approach. CONCLUSION: Identifying and treating women ≥70 years of age with osteopenia and microstructural deterioration with zoledronate cost-effectively reduces the morbidity and mortality imposed by fragility fractures. This 'targeted' approach is more cost-effective than a 'global' approach and incurs only 25% of total costs. IMPLICATION: Women with osteopenia with bone fragility due to microstructural deterioration should be identified and targeted for treatment. SUMMARY: Women with osteopenia have 70% of fractures. Treating those with microstructural deterioration conferred an incremental cost-effectiveness ratio of $4992/year of life saved and $6135 per QALY saved.

Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis.

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Determining individual trajectories of joint space loss: improved statistical methods for monitoring knee osteoarthritis disease progression.

OBJECTIVES: Knee osteoarthritis (KOA) progression is frequently monitored by calculating the change in knee joint space width (JSW) measurements. Such differences are small and sensitive to measurement error. We aimed to assess the utility of two alternative statistical modelling methods for monitoring KOA. MATERIAL AND METHODS: We used JSW on radiographs from both the control arm of the Strontium Ranelate Efficacy in Knee Osteoarthritis trial (SEKOIA), a 3-year multicentre, double-blind, placebo-controlled phase three trial, and the Osteoarthritis Initiative (OAI), an open-access longitudinal dataset from the USA comprising participants followed over 8 years. Individual estimates of annualised change obtained from frequentist linear mixed effect (LME) and Bayesian hierarchical modelling, were compared with annualised crude change, and the association of these parameters with change in WOMAC pain was examined. RESULTS: Mean annualised JSW changes were comparable for all estimates, a reduction of around 0.14 mm/y in SEKOIA and 0.08 mm/y in OAI. The standard deviation (SD) of change estimates was lower with LME and Bayesian modelling than crude change (SEKOIA SD = 0.12, 0.12 and 0.21 respectively; OAI SD = 0.08, 0.08 and 0.11 respectively). Estimates from LME and Bayesian modelling were statistically significant predictors of change in pain in SEKOIA (LME P-value = 0.04, Bayes P-value = 0.04), while crude change did not predict change in pain (P-value = 0.10). CONCLUSIONS: Implementation of LME or Bayesian modelling in clinical trials and epidemiological studies, would reduce sample sizes by enabling all study participants to be included in analysis regardless of incomplete follow up, and precision of change estimates would improve. They provide increased power to detect associations with other measures.

GNAS mutated thyroid carcinoma in a patient with Mc Cune Albright syndrome.

Mc Cune-Albright syndrome (MAS) is a rare disorder defined by the triad of polyostotic fibrous dysplasia, "café au lait" skin hyperpigmentation and hyperfunctioning endocrinopathies, such as precocious puberty. MAS is caused by an activating post zygotic somatic mutation of GNAS gene, coding for the alpha-subunit of the stimulatory G protein (Gsalpha). In endocrine tissues, this mutation results in overproduction of hormones and endocrine cell hyperfunction and proliferation. Whereas the association of hyperthyroidism and thyroid adenomas is well known in MAS, the relation with thyroid carcinoma has rarely been observed. We report the occurrence of a thyroid carcinoma in an 18-years old woman with MAS, revealed by subclinical hyperthyroidism detected during her systematic annual follow-up. Ultrasound and thyroid scintigraphy revealed the presence of a nodule in the right lobe. Pathology on hemithyroidectomy revealed an unexpected thyroid follicular carcinoma. Neoplastic thyroid cells harbored the GNAS R201C activating mutation. This observation suggests that MAS may predispose patients to thyroid carcinomas and supports the importance of thyroid assessment by physical examination, hormonal blood test and ultrasound, in the follow-up of patients with MAS. Because ultrasound diagnostic is challenging in MAS, needle puncture of palpable nodules should be advised.