Management of bone fragility in patients with rheumatoid arthritis in France: An analysis of a national health insurance claims database.

OBJECTIVES: Rheumatoid arthritis (RA) is considered a major risk factor for fragility fractures. We examined the quality of management of bone fragility in RA patients in a real-life setting. METHODS: We performed a longitudinal case-control retrospective study in a 1/97th random sample of French health care claims database from 2014 to 2016 to determine the extent of bone fragility management in patients with RA compared with non-RA matched controls. RESULTS: Compared to their non-RA controls (n=4652), RA patients (n=1008; mean age: 61.1years; methotrexate: 69.7%; other conventional disease-modifying antirheumatic drugs (cDMARDs): 26.8%; biologic: 26.0%; corticosteroids: 36.9%) had more reimbursements for bone mineral density (BMD) measurements (21.6 vs. 9.2%; OR=2.7 [2.3; 3.3]; P<0.01) and for bisphosphonates (7.1 vs. 3.6%, OR=2.0 [1.5; 2.7]; P<0.05). In patients exposed to corticosteroids, RA patients underwent more BMD assessments than non-RA controls (28.0 vs. 18.8%; OR=1.7 [1.3; 2.2]; P<0.05). RA patients exposed to corticosteroids were more likely to sustain fracture than non-exposed RA patients (5.7 vs. 2.4%, P<0.01). In addition, only when comparing patients exposed to corticosteroids, was there statistical evidence of an association between RA and an increased fracture rate (6.2 vs. 3.5%, P<0.05). CONCLUSION: Patients with RA exposed to corticosteroids are at high risk of fracture. Patients with RA had more bone fragility management than controls.

Adherence to and patient's knowledge of self-management of subcutaneous biologic therapy in chronic inflammatory rheumatic diseases: results of a multicentre cross-sectional study.

OBJECTIVES: Non-adherence to biologic therapy is an issue in chronic inflammatory rheumatic diseases (CIRDs) and might be related to poor patient knowledge of the risk of these therapies. Our aim here was to evaluate the level of patient adherence to and knowledge of self-care safety skills for biologic therapy. METHODS: This was a multicentre, cross-sectional study in which out-patients visited an office- or hospital-based rheumatologist. All the patients received subcutaneous biologic therapy for CIRDs. We collected data on: 1. the level of CIRD patient adherence to current subcutaneous biologic therapy using both the self-administered Compliance Questionnaire Rheumatology 5 items (CQR5) and a simple adherence question; 2. patients' knowledge of self-management of biologic therapy by the self-administered BIOSECURE questionnaire; 3. sources of information related to biologic therapy. RESULTS: In all, 285 patients (rheumatoid arthritis, n=103; spondyloarthritis, n=153; psoriatic arthritis, n=25) were enrolled by 19 rheumatologists. The mean (SD) biologic therapy duration was 5.9 (4.9) years. Adherence to the current biologic therapy was high (79.3% and 57.5% according to the CQR5 questionnaire and the adherence question, respectively). Level of knowledge of self-care safety skills (median BIOSECURE score 71) was in the acceptable range. Level of adherence and level of knowledge of self-care safety skills for biologic therapy were not associated. Patients declared that the main sources of information were their rheumatologist (92.6%) and the rheumatology team (30.5%). CONCLUSIONS: According to the patients' estimation, adherence to biologic therapy and the level of knowledge of self-care safety skills related to biologic therapy are acceptable, and these domains are not related (e.g. level of adherence and level of knowledge of risks).

Vertebral strength prediction from Bi-Planar dual energy x-ray absorptiometry under anterior compressive force using a finite element model: An in vitro study.

Finite element models (FEM) derived from qCT-scans were developed as a clinical tool to evaluate vertebral strength. However, the high dose, time and cost of qCT-scanner are limitations for routine osteoporotic diagnosis. A new approach considers using bi-planar dual energy (BP2E) X-rays absorptiometry to build vertebral FEM using synchronized sagittal and frontal plane radiographs. The purpose of this study was to compare the performance of the areal bone mineral density (aBMD) measured from DXA, qCT-based FEM and BP2E-based FEM in predicting experimental vertebral strength. Twenty eight vertebrae from eleven lumbar spine segments were imaged with qCT, DXA and BP2E X-rays before destructively tested in anterior compression. FEM were built based on qCT and BP2E images for each vertebra. Subject-specific FEM were built based on 1) the BP2E images using 3D reconstruction and volumetric BMD distribution estimation and 2) the qCT scans using slice by slice segmentation and voxel based calibration. Linear regression analysis was performed to find the best predictor for experimental vertebral strength (Fexpe); aBMD, modeled vertebral strength and vertebral stiffness. Areal BMD was moderately correlated with Fexpe (R2 = 0.74). FEM calculations of vertebral strength were highly to strongly correlated with Fexpe (R2 = 0.84, p < 0.001 for BP2E model and R2 = 0.95, p < 0.001 for qCT model). The results of this study suggest that aBMD accounted for only 74% of Fexpe variability while FE models accounted for at least 84%. For anterior compressive loading on isolated vertebral bodies, simplistic loading condition aimed to replicate anterior wedge fractures, both FEM were good predictors of Fexpe. Therefore FEM based on BP2E X-rays absorptiometry could be a good alternative to replace qCT-based models in the prediction of vertebral strength. However future work should investigate the performance of the BP2E-based model in vivo in discriminating patients with and without vertebral fracture in a prospective study.

Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms.

OBJECTIVE: Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults. PATIENTS AND METHODS: We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL. RESULTS: Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09-18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03-0.57), P=0.007 and OR=0.26 (0.07-0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05). CONCLUSION: Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.

Vitamin D status and bone mineral density changes during alendronate treatment in postmenopausal osteoporosis.

Vitamin D supplementation is recommended for women with osteoporosis. In the FOCUS-D trial comparing the combination tablet alendronate plus vitamin D3 5,600 IU (ALN/D) with standard care (SC) prescribed by patients' personal physicians, ALN/D was more effective in improving serum 25(OH)D and bone turnover markers by 6 months and increasing spine and hip bone mineral density (BMD) after 1 year than SC. This post hoc analysis examined the relationship between BMD gain and 25(OH)D in women in SC receiving alendronate (SC/ALN, n = 134, 52% of the SC group) and in the ALN/D group (n = 257). At baseline, participants were of mean age 73 years and 72% were Caucasian, with a mean 25(OH)D of 14.9 ng/mL. In the SC/ALN group, most received vitamin D, although intake of vitamin D varied extensively (51% received <400 µg/day). In this group, end-of-study 25(OH)D correlated positively with mean percent increases from baseline in lumbar spine and femoral neck BMD [Pearson correlation coefficients (95% CI) = 0.23 (0.02-0.41) and 0.24 (0.03-0.41), respectively]. Baseline 25(OH)D correlated with increases in only lumbar spine BMD [Pearson correlation coefficient (95% CI) = 0.22 (0.01-0.40)]. No correlations between mean BMD change and 25(OH)D were seen with ALN/D. In conclusion, in postmenopausal women with osteoporosis and low 25(OH)D receiving alendronate and a wide range of vitamin D doses, the increase in lumbar spine and femoral neck BMD was positively correlated with serum 25(OH)D achieved by the end of the study and, to some extent, with 25(OH)D concentrations at baseline. The degree of success of alendronate therapy for osteoporosis may depend on the vitamin D status of patients.

Bone turnover and bone mineral density are independently related to selenium status in healthy euthyroid postmenopausal women.

CONTEXT: Selenium status may have direct effects on bone and indirect effects through changes in thyroid hormone sensitivity. OBJECTIVE: We hypothesized that variation in selenium status in healthy euthyroid postmenopausal women is associated with differences in bone turnover, bone mineral density (BMD) and fracture susceptibility. DESIGN: The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. SETTING: The study was comprised of a population-based cohort from five European cities. PARTICIPANTS: A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1144. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: We measured selenium (micrograms per liter); selenoprotein P (milligrams per liter); free T(4) (picomoles per liter); free T(3) (picomoles per liter); TSH (milliunits per liter); bone turnover markers; BMD; and vertebral, hip, and nonvertebral fractures. RESULTS: Higher selenium levels were associated with higher hip BMD at study entry (ß = 0.072, P = 0.004) and lower levels of bone formation (osteocalcin: ß = -0.101, P < 0.001; procollagen type 1 N-terminal propeptide: ß = -0.074, P = 0.013) and resorption markers (C-telopeptide of type 1 collagen: ß = -0.058, P = 0.050; N-telopeptide of type 1 collagen: ß = -0.095, P = 0.002). Higher selenoprotein P was associated with higher hip (ß = 0.113, P < 0.001) and lumbar spine BMD (ß = 0.088, P = 0.003) at study entry, higher hip BMD after the 6-yr follow-up (ß = 0.106, P = 0.001) and lower osteocalcin (ß = -0.077, P = 0.009), C-telopeptide of type 1 collagen (ß = -0.075, P = 0.012), and N-telopeptide of type 1 collagen (ß = -0.110, P < 0.001). CONCLUSION: Selenium status is inversely related to bone turnover and positively correlated with BMD in healthy euthyroid postmenopausal women independent of thyroid status.

Randomized trial of alendronate plus vitamin D3 versus standard care in osteoporotic postmenopausal women with vitamin D insufficiency.

Vitamin D insufficiency is common in patients with osteoporosis. We conducted a randomized trial comparing alendronate 70 mg combined with vitamin D(3) 5,600 IU in a single tablet (ALN/D5600, n = 257) with standard care chosen by the patients' personal physicians (n = 258) in patients with postmenopausal osteoporosis (BMD T score ≤2.5 or ≤1.5 and a prior fragility fracture) who had vitamin D insufficiency (serum 25[OH]D values 8-20 ng/ml) and who were at risk of falls. Virtually all patients randomized to standard care received bisphosphonate therapy, and in approximately 70% of cases this was combined with vitamin D supplements. However, only 24% took ≥800 IU/day of supplemental vitamin D. At 6 months the proportion of patients with vitamin D insufficiency was 8.6% in the ALN/D5600 group compared with 31.0% in the standard care group (P < 0.001). Those in the ALN/D5600 group also had a greater reduction in urinary NTX/creatinine ratio (-57% vs. -46%, P < 0.001) and bone-specific alkaline phosphatase (-47% vs. -40%, P < 0.001). In the ALN/5600 group, by 12 months the increase in BMD was greater at the lumbar spine (4.9% vs. 3.9%, P = 0.047) and the total hip (2.2% vs. 1.4%, P = 0.035), significantly fewer patients were vitamin D-insufficient (11.3% vs. 36.9%, P < 0.001), and bone turnover marker (BTM) results were similar to those at 6 months. There was no difference between groups in those who experienced falls or fractures, and adverse events were similar. Based on the finding that ALN/D5600 was more effective than standard care at correcting vitamin D insufficiency, increasing BMD, and reducing BTMs in this patient group, greater attention needs to be directed toward optimizing the treatment of osteoporosis and correcting vitamin D deficiency in postmenopausal women.

Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density.

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.

Bone status in primary hyperparathyroidism assessed by regional bone mineral density from the whole body scan and QUS imaging at calcaneus.

To assess the bone mineral density status in primary hyperparathyroidism (PHPT), we studied 64 females with PHPT and 17 healthy women. Regional BMD (arms, trunk, legs) from the whole body scan and conventional sites (lumbar spine, femur, radius) were assessed by DXA. Quantitative ultrasound (QUS) imaging measurements were performed at calcaneus. Sixteen women had history of renal lithiasis, 11 had low impact fracture and 37 women had neither renal lithiasis nor fracture. In the entire group, the mean Z-scores were significantly decreased at all sites (lumbar spine, femur, radius). In all clinical subgroups, the mean Z-scores were significantly decreased at radius. The mean Z-scores in premenopausal women were significantly decreased comparatively to postmenopausal women at lumbar spine and femur. In a group of PHPT females matched to controls for age and BMI, only BMD values at radius were lower in PHPT patients than in control (P < 0.03). However, from the whole body scan data, all sites but no trunk were significantly involved in PHPT patients (P < 0.04). Using QUS measurements at calcaneus, the BUA but not SOS in PHPT females was significantly lower (P = 0.03) than in controls. Our results suggest that low BMD at lumbar spine and femur is encountered preferentially in premenopausal women. The BMD decrease predominates at limbs in PHPT with presumably a gradient from proximal to distal part of the limbs. Indeed, the distal part of the limbs are the most affected areas in PHPT whatever the amount of cortical or trabecular bone.

Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials.

UNLABELLED: The incidences of osteoporosis and renal insufficiency increase with age. We studied the influence of renal function on the safety and efficacy of risedronate 5 mg daily in osteoporotic women. Risedronate was safe and effective in osteoporotic women with mild, moderate, or severe age-related renal impairment. INTRODUCTION: The incidences of both osteoporosis and renal insufficiency increase with age; thus, the effect of renal impairment on the safety and efficacy of osteoporosis treatments is a clinical concern. Risedronate is a pyridinyl bisphosphonate well established as safe and effective in the treatment and prevention of osteoporosis. Currently, there is little available information about the effect of bisphosphonate treatment in patients with renal insufficiency. This retrospective analysis was conducted to study the influence of renal function on the safety and efficacy of risedronate in a population of osteoporotic women. MATERIALS AND METHODS: Combined data from nine randomized, double-blind, placebo-controlled phase III risedronate trials were analyzed. The patients in these studies had no markedly abnormal laboratory parameters that were considered clinically significant and no evidence of significant disease. This analysis included patients who received placebo (n = 4,500) or risedronate 5 mg (n = 4,496) for up to 3 years (average duration of exposure, 2 years) and who had renal impairment (creatinine clearance [CrCl] < 80 ml/min). CrCl was estimated by the Cockcroft and Gault method, based on age, weight, and serum creatinine. Patients were categorized as having mild (CrCl >or=50 to <80 ml/min), moderate (CrCl >or=30 to <50 ml/min), or severe (CrCl < 30 ml/min) renal impairment. RESULTS: Of the patients studied, renal impairment at baseline was mild in 48% (mean [range] serum creatinine, 0.9 [0.4-1.6] mg/dl), moderate in 45% (1.1 [0.6-1.9] mg/dl), and severe in 7% (1.3 [0.7-2.7] mg/dl). In both the placebo and risedronate treatment groups, the patients with the most severe renal impairment were older and had more severe osteoporosis. The incidences of overall adverse events and of renal function-related adverse events were similar in the placebo and risedronate 5 mg groups regardless of renal function. Furthermore, evaluation of changes from baseline in serum creatinine revealed no difference in renal function between the placebo and risedronate 5 mg groups in any of the renal impairment subgroups at any time-point. In all three subgroups, risedronate effectively preserved BMD and reduced the incidence of vertebral fractures. CONCLUSIONS: These findings show that risedronate is safe and effective in osteoporotic women with age-related mild, moderate, or severe renal impairment.

Benefits of pamidronate in children with osteogenesis imperfecta: an open prospective study.

OBJECTIVES: To study the efficacy of pamidronate in children with osteogenesis imperfecta (OI). PATIENTS AND METHODS: Twenty-nine patients (median age 8.7 years), were given pamidronate in cyclic infusions of 3 days. Patients received 3-13 cycles (median 6), at a dose of 0.5 mg/kg/day in infants (below 2 years of age) and 1 mg/kg/day in children (2 years and older). The interval time between cycles was 2 months in infants and 4 months in children. The median follow-up was 16 months. All patients received daily supplementation of calcium, vitamin D and physical rehabilitation. Assessments were performed at baseline and before each cycle. Fracture rate under treatment was compared to the one in the pre-treatment period. RESULTS: Pain decreased after the first infusion cycle (P < 0.0001). The median of fracture incidence decreased from 15 to 0.5 per year in infants and from 2.0 to 1 per year in children (P = 0.04). Alkaline phosphatase decreased by 31.2% and N-telopeptide collagen cross-links decreased by 61.8% (P < 0.001). Bone mineral density (BMD) of the spine increased by a median of 55.4% (P < 0.001). Z-scores increased from a median of -4.7 to -2.6 (P < 0.001). The femoral neck, BMD increased by a median of 16%. The area of the first four lumbar vertebrae increased by a median of 21.5% (P < 0.001). No adverse effect on growth or on fracture healing was observed. Side effects were symptomatic hypocalcemia in one infant, and the transient acute phase reaction. CONCLUSION: Pamidronate increases BMD, decreases bone remodeling markers, pain and fracture rate in infants and children with OI.

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

BACKGROUND: Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. METHODS: To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. RESULTS: New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. CONCLUSIONS: Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.