[Show abstract][Hide abstract] ABSTRACT: Objective:
To perform an external validation of FRAX algorithm thresholds for reporting level of risk of fracture in Spanish women (low <5%; intermediate ≥5% and <7.5%; high ≥7.5%) taken from a prospective cohort "FRIDEX".
A retrospective study of 1090 women aged ≥40 and ≤90 years old obtained from the general population (FROCAT cohort). FRAX was calculated with data registered in 2002. All fractures were validated in 2012. Sensitivity analysis was performed.
When analyzing the cohort (884) excluding current or past anti osteoporotic medication (AOM), using our nominated thresholds, among the 621 (70.2%) women at low risk of fracture, 5.2% [CI95%: 3.4-7.6] sustained a fragility fracture; among the 99 at intermediate risk, 12.1% [6.4-20.2]; and among the 164 defined as high risk, 15.9% [10.6-24.2]. Sensitivity analysis against model risk stratification FRIDEX of FRAX Spain shows no significant difference. By including 206 women with AOM, the sensitivity analysis shows no difference in the group of intermediate and high risk and minimal differences in the low risk group.
Our findings support and validate the use of FRIDEX thresholds of FRAX when discussing the risk of fracture and the initiation of therapy with patients.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis.
This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17β-estradiol levels by radioimmunoassay based on ultrasensitive methods.
In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure.
Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis.
[Show abstract][Hide abstract] ABSTRACT: The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies.
Calcified Tissue International 08/2015; DOI:10.1007/s00223-015-0050-1 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although a number of reports suggest very low persistence with oral bisphosphonates, there is limited data on persistence with other anti-osteoporosis medications. We compare rates of early discontinuation (in the first year) with all available outpatient anti-osteoporosis drugs in Catalonia, Spain. We conducted a population-based retrospective cohort study using data from the SIDIAP database. SIDIAP contains computerized primary care records and pharmacy dispensing data for >80 % of the population of Catalonia (>5 million people). All SIDIAP participants starting an anti-osteoporosis drug between 1/1/2007 and 30/06/2011 (with 2 years wash-out) were included. We modelled persistence as the time between first prescription and therapy discontinuation (refill gap of at least 6 months) using Fine and Gray survival models with competing risk for death. We identified 127,722 patients who started any anti-osteoporosis drug in the study period. The most commonly prescribed drug was weekly alendronate (N = 55,399). 1-Year persistence ranges from 40 % with monthly risedronate to 7.7 % with daily risedronate, and discontinuation was very common [from 49.5 % (monthly risedronate) to 84.4 % (daily risedronate)] as was also switching in the first year of therapy [from 2.8 % (weekly alendronate) to 10 % (daily alendronate)]. Multivariable-adjusted models showed that only monthly risedronate had better one-year persistence than weekly alendronate and teriparatide equivalent, whilst all other therapies had worse persistence. Early discontinuation with available anti-osteoporosis oral drugs is very common. Monthly risedronate, weekly alendronate, and daily teriparatide are the drugs with the best persistence, whilst daily oral drugs have 40-60 % higher first-year discontinuation rates compared to weekly alendronate.
Calcified Tissue International 07/2015; DOI:10.1007/s00223-015-0040-3 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oral bisphosphonates (BPs) are highly effective in preventing fractures and are recommended first-line therapies for patients with osteoporosis. We identified the incidence and predictors of oral BP treatment failure, defined as the incidence of ≥2 fractures while on treatment (≥2 FWOT) among users with high adherence. Fractures were considered after six months from treatment initiation and up to six months after discontinuation. Data from computerized records and pharmacy invoices were obtained from Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP) (Catalonia, Spain) and Danish Health Registries (Denmark) for all incident users of oral BPs in 2006-2007 and 2000-2001 respectively. Fine and Gray survival models using backward-stepwise selection (p-entry 0.049; p-exit 0.10) and accounting for the competing risk of therapy cessation were used to identify predictors of ≥2 FWOT among patients having persisted with treatment ≥6months with overall medication possession ratio (MPR) ≥80%. Incidence of ≥2 FWOT was 2.4 (95% Confidence Interval (CI): 1.8-3.2) and 1.7 (95% CI: 1.2-2.2) per 1000 Person Years (PYs) within Catalonia and Denmark respectively. Older age was predictive of ≥2FWOT in both Catalonian and Danish cohorts: subhazard ratio (SHR) = 2.28 (95% CI: 1.11-4.68) and SHR = 2.61 (95% CI: 0.98-6.95) respectively for 65 to <80 years and SHR = 3.19 (95% CI: 1.33-7.69) and SHR = 4.88 (95% CI: 1.74-13.7) respectively for ≥80 years. Further significant predictors of ≥2 FWOT identified within only one cohort were dementia, SHR = 4.46 (95% CI: 1.02-19.4) (SIDIAP) and history of recent or older fracture, SHR = 3.40 (95% CI: 1.50-7.68) and SHR = 2.08 (95% CI: 1.04-4.15) respectively (Denmark). Even among highly adherent users of oral BP therapy, a minority sustain multiple fractures while on treatment. Older age was predictive of increased risk within both study populations, as was history of recent/old fracture and dementia within one but not both populations. Additional and/or alternative strategies should be investigated for these patients. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2015; DOI:10.1002/jbmr.2595 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the B-ABLE cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (p<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of aromatase inhibitor-induced bone loss.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids, widely used in inflammatory disorders, rapidly increase bone fragility and, therefore, fracture risk. However, common bone densitometry measurements are not sensitive enough to detect these changes. Moreover, densitometry only partially recognizes treatment-induced fracture reductions in osteoporosis. Here, we tested whether the reference point indentation, technique could detect bone tissue properties changes early after glucocorticoid treatment initiation. After initial laboratory and bone density measurements, patients were allocated into groups receiving calcium + vitamin D (Ca + D) supplements or anti-osteoporotic drugs (risedronate, denosumab, teriparatide). Reference point indentation was performed on the cortical bone layer of the tibia by a handheld device measuring Bone Material Strength index (BMSi). Bone mineral density was measured by dual-energy x-ray absorptiometry (DXA). While Ca + D-treated patients exhibited substantial and significant deterioration, risedronate-treated patients exhibited no significant change, and both denosumab- and teriparatide-treated participants exhibited significantly improved BMSi 7 weeks after initial treatment compared to baseline; these trends remained stable for 20 weeks. In contrast, no densitometry changes were observed during this study period. In conclusion, our study is the first to demonstrate that reference point indentation is sensitive enough to reflect changes in cortical bone indentation following treatment with osteoporosis therapies in patients newly exposed to glucocorticoids. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2015; 30(9). DOI:10.1002/jbmr.2497 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
In clinical trials, bisphosphonate therapy reduces but does not eliminate the risk of fracture. The objective of this retrospective observational study was to examine fracture rates among women who were adherent to bisphosphonate therapy for at least 1 year.
We studied outcomes for women ≥50 years old who received their first osteoporosis therapy as an oral bisphosphonate during 2002-2008 and were enrolled in a large claims database for ≥3 consecutive years, including a baseline year before and 2 years after the index prescription (thus, the full study period was 2001-2010). Adherence during the first year of therapy was defined as a medication possession ratio (MPR) ≥80% (total number of days' supply/365 days × 100%).
Of the 62,446 women who met the eligibility criteria, 26,852 (43%) had an MPR ≥80% for osteoporosis therapy during year 1. In year 2, the fracture rate was 52/1000 patient-years. Fragility fractures were recorded for 1292 patients (4.8%) during the baseline year (before initiating therapy); for 1051 patients (3.9%) during year 1 (adherence year); and for 871 patients (3.2%) during year 2. Significant predictors of fracture in year 2 were older age, higher comorbidity score, comorbid inflammatory joint disease, and prior fragility fracture during the baseline year or first year of treatment. The primary limitation of these results is the scope of the claims database, which did not provide information on bone mineral density, supplemental use of calcium or vitamin D, or reasons for initiating oral bisphosphonates.
Despite being adherent to bisphosphonate treatment for 1 year, 3.2% of women experienced a fracture in the subsequent year. These results suggest an unmet need in patients with osteoporosis and an opportunity for newer therapies to help address this need.
Current Medical Research and Opinion 02/2015; 31(4):1-36. DOI:10.1185/03007995.2015.1016606 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context. Several fracture prediction models that combine fractures at different sites into a composite outcome are in current use. However, to the extent individual fracture sites have differing risk factor profiles, model discrimination is impaired. Objective. To improve model discrimination by developing a 5-yr composite fracture prediction model for fracture sites that display similar risk profiles. Design. Prospective, observational cohort study. Setting. Primary care practices in 10 countries. Patients. Women aged ≥55 years. Intervention. Self-administered questionnaires collected data on patient characteristics, fracture risk factors and previous fractures. Main Outcome Measure. Main outcome is time to first clinical fracture of hip, pelvis, upper leg, clavicle, or spine, each of which exhibits a strong association with advanced age. Results. Of four composite fracture models considered, model discrimination (c index) is highest for an age-related fracture model (c index 0.75, 47,066 women), and lowest for FRAX major fracture and a 10-site model (c indices 0.67 and 0.65). The unadjusted increase in fracture risk for an additional 10 yr of age ranges from 80% to 180% for the individual bones in the age-associated model. Five other fracture sites not considered for the age-associated model (upper arm/shoulder, rib, wrist, lower leg, and ankle) have age associations for an additional 10 yr of age from a 10% decrease to a 60% increase. Conclusions. After examining results for 10 different bone fracture sites, advanced age appeared the single best possibility for uniting several different sites, resulting in an empirically based composite fracture risk model.
The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133468. DOI:10.1210/jc.2013-3468 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Summary There is scarce data on the association between early stages of type 2 diabetes and fracture risk. We report a 20 % excess risk of hip fracture in the first years following disease onset compared to matched non-diabetic patients. Introduction Type 2 diabetes mellitus (T2DM) is a chronic disease that affects several target organs. Data on the association between T2DM and osteoporotic fractures is controversial. We estimated risk of hip fracture in newly diagnosed T2DM patients, compared to matched non-diabetic peers. Methods We conducted a population-based parallel cohort study using data from the Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP) database. Participants were all newly diagnosed T2DM patients registered in SIDIAP in 2006–2011 (T2DM cohort). Up to two diabetes-free controls were matched to each T2DM participant on age, gender, and primary care practice. Main outcome was incident hip fracture in 2006–2011, ascertained using the tenth edition of the International Classification of Diseases (ICD-10) codes. We used Fine and Gray survival modelling to estimate risk of hip fracture according to T2DM status, accounting for competing risk of death. Multivariate models were adjusted for body mass index, previous fracture, and use of oral corticosteroids. Results During the study period (median follow-up 2.63 years), 444/58,483 diabetic patients sustained a hip fracture (incidence rate 2.7/1,000 person-years) compared to 776/113,448 matched controls (2.4/1,000). This is equivalent to an unadjusted (age- and gender-matched) subhazard ratio (SHR) 1.11 [0.99–1.24], and adjusted SHR 1.20 [1.06–1.35]. The adjusted SHR for major osteoporotic and any osteoporotic fractures were 0.95 [0.89–1.01] and 0.97 [0.92–1.02]. Conclusions Newly diagnosed T2DM patients are at a 20 % increased risk of hip fracture even in early stages of disease, but no for all fractures. More data is needed on the causes for an increased fracture risk in T2DM patients as well as on the predictors of osteoporotic fractures among these patients.
Osteoporosis International 12/2014; 26(2). DOI:10.1007/s00198-014-2986-9 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is commonly associated with menopause and ageing. It can, however, also be caused by diseases, lifestyle, genetic diseases, drug therapies and other therapeutic interventions. In cases of secondary osteoporosis, a common rule is the management of the underlying condition. Healthy habits and calcium and vitamin D supplementation are also generally advised. In cases of high risk of fracture, specific antiosteoporosis medications should be prescribed. For most conditions, the available evidence is limited. Special attention should be paid to possible contraindications of drugs used for the treatment of postmenopausal or senile osteoporosis. Bisphosphonates are the most widely used drugs in secondary osteoporosis, and denosumab or teriparatide have been also assessed in some cases. Important research is needed to develop more tailored strategies, specific to the peculiarities of the different types of secondary osteoporosis.
Best Practice & Research: Clinical Endocrinology & Metabolism 12/2014; 28(6). DOI:10.1016/j.beem.2014.09.004 · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: From 50 years of age, postmenopausal women are at an increased risk of developing sarcopenia and osteoporosis as a result of deterioration of musculoskeletal health. Both disorders increase the risk of falls and fractures. The risk of developing sarcopenia and osteoporosis may be attenuated through healthy lifestyle changes, which include adequate dietary protein, calcium and vitamin D intakes, and regular physical activity/exercise, besides hormone replacement therapy when appropriate. Protein intake and physical activity are the main anabolic stimuli for muscle protein synthesis. Exercise training leads to increased muscle mass and strength, and the combination of optimal protein intake and exercise produces a greater degree of muscle protein accretion than either intervention alone. Similarly, adequate dietary protein intake and resistance exercise are important contributors to the maintenance of bone strength. Vitamin D helps to maintain muscle mass and strength as well as bone health. These findings suggest that healthy lifestyle measures in women aged >50 years are essential to allow healthy aging. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommends optimal dietary protein intake of 1.0–1.2 g/kg body weight/d with at least 20–25 g of high-quality protein at each main meal, with adequate vitamin D intake at 800 IU/d to maintain serum 25-hydroxyvitamin D levels >50 nmol/L as well as calcium intake of 1000 mg/d, alongside regular physical activity/exercise 3–5 times/week combined with protein intake in close proximity to exercise, in postmenopausal women for prevention of age-related deterioration of musculoskeletal health.
[Show abstract][Hide abstract] ABSTRACT: Ankylosing spondylitis (AS) leads to osteopenia/osteoporosis and spine rigidity. We conducted a case-control study and found that AS-affected patients have a 5-fold and 50 % increased risk of clinical spine and all clinical fractures, respectively. Excess risk of both is highest in the first years and warrants an early bone health assessment after diagnosis.
Osteoporosis International 10/2014; 26(1). DOI:10.1007/s00198-014-2939-3 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Patients with OA use different drugs in their search for relief. We aimed to study the prevalence of use and combinations of different medications for OA in a population-based cohort of OA patients in Catalonia, Spain, while characterizing users of each of the drugs available, with a particular focus on cardiovascular risk factors.
Data were obtained from the Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària (SIDIAP) database, which includes electronic medical records and pharmacy invoice data for >5 million people from Catalonia. Study participants were those with a clinical diagnosis of OA in 2006-10. Drugs studied included oral and topical NSAIDs, analgesics (paracetamol, metamizole), opioids (tramadol, fentanyl), cyclooxygenase 2 (COX-2) inhibitors and symptomatic slow-acting drugs in OA. Drug utilization was described using medication possession ratios (MPRs), equivalent to the proportion of days covered with the drug of interest. The annual incidence of new users in the first year after OA diagnosis from 2006 to 2010 was estimated for all studied drugs among newly diagnosed OA patients using Poisson regression.
We identified 238 536 study participants. The most common regimen of treatment consisted of at least three drugs (53.9% of patients). The drugs most frequently used regularly (MPR ≥50%) were chondroitin (21.2%), glucosamine (15.8%) and oral NSAIDs (14.4%). The incidence of the use of opioids, COX-2 inhibitors and chondroitin increased over the 5 year period, whereas all others decreased.
Drug combinations are common in the treatment of OA patients, who are thus exposed to potential drug interactions, with unknown impacts on their health. The increasing use of opioids and COX-2 inhibitors is noteworthy because of the potential impact on safety and costs.