Calcium channel blocker-clarithromycin drug interaction did not increase the risk of nonvertebral fracture: a population-based study.

BACKGROUND: Calcium channel blocker (CCB) use in elderly patients lowers blood pressure and can increase the risk of falls and fractures. These drugs are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme, and blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4, whereas azithromycin is not. OBJECTIVE: In older patients taking a CCB, we investigated whether coprescription of clarithromycin, compared with azithromycin, was associated with a higher risk of fracture. METHODS: This was a population-level retrospective cohort study in Ontario, Canada, from 2003 to 2012 of older adults (mean age = 76 years) newly prescribed clarithromycin (n = 96 226) or azithromycin (n = 94 083) while taking a CCB (amlodipine, nifedipine, felodipine, verapamil, diltiazem). The outcome assessed within 30 days of a new coprescription was a nonvertebral fracture. RESULTS: There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed CCB (more than 50% of patients). Coprescribing clarithromycin, versus azithromycin, was not associated with a higher 30-day risk of nonvertebral fracture (124 patients of 96 226 taking clarithromycin [0.13%] vs 98 patients of 94 083 taking azithromycin [0.10%]; odds ratio = 1.23 [95% CI = 0.94-1.60]; P = 0.134). CONCLUSIONS: Among older adults taking a CCB, concurrent use of clarithromycin, compared with azithromycin, was not associated with a statistically significantly greater 30-day risk of nonvertebral fracture.

Osteoporotic fractures in patients with untreated hyperprolactinemia vs. those taking dopamine agonists: A systematic review and meta-analysis.

OBJECTIVE: Hyperprolactinemia is associated with bone fragility. Traditionally attributed to prolactin-induced hypogonadism, recent studies have identified increased fracture rates independent of gonadal function. METHODS: We performed a systematic review to identify studies assessing fracture risk in patients with untreated hyperprolactinemia compared to those on dopamine agonists. MEDLINE, EMBASE, Cochrane, Web of Science and BIOSIS Previews databases were searched from inception to December 2013 for studies of hyperprolactinemia with fractures as an outcome. Two authors independently performed title and abstract searches, full-text searches, data abstraction, and quality assessment. A summary odds ratio (OR) was calculated using a random effects model. RESULTS: Of the 197 articles identified, 2 met inclusion criteria. Both cross-sectional studies examined cabergoline use (or non-use) in patients with prolactin-secreting adenomas, with vertebral fractures as the primary outcome. For women, vertebral fractures were identified in 46% of untreated patients, vs. 20% of patients on cabergoline (OR: 0.29, 95% CI: 0.10-0.78). For men, the results were 67% in untreated, vs. 26% in cabergoline treated patients (OR: 0.18, CI: 0.03-0.94), with no difference between gonadal and hypogonadal men (p=0.8). Combining studies gave a summary odds ratio of 0.25 (CI: 0.11-0.59), I2=0%. CONCLUSIONS: In the limited studies available, fracture prevalence was increased in patients with untreated hyperprolactinemia compared to those on treatment, independent of gonadal function. Further studies are needed to clarify if post-menopausal women, or high-risk men, with no other indication for treatment, should be on dopamine agonists to decrease fracture risk.

The three-year incidence of fracture in chronic kidney disease.

Knowing a person's fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2)), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials.

Effect of Anticholinergic Medications on Falls, Fracture Risk, and Bone Mineral Density Over a 10-Year Period.

BACKGROUND: Many medications used in older adults have strong anticholinergic (ACH) properties, which may increase the risk of falls and fractures. Use of these medications was identified in a population-based Canadian cohort. OBJECTIVE: To identify the fall and fracture risk associated with ACH medication use. METHODS: Data collection and analysis were conducted at baseline, year 5, and year 10. Cross-sectional analyses were performed to examine associations between ACH medication use and falls. Time-dependent Cox regression was used to examine time to first nontraumatic fracture. Finally, change in bone mineral density (BMD) over 10 years was compared in ACH medication users versus nonusers. RESULTS: Strongly ACH medications were used by 618 of 7753 participants (8.0%) at study baseline, 592 (9.5%) at year 5, and 334 (7.7%) at year 10. Unadjusted ACH medication use was associated with falls at baseline (odds ratio = 1.50; 95% CI = 1.14-1.98; P = 0.004), but the association was no longer significant after covariate adjustment. Similar results occurred at years 5 and 10. ACH medication use was associated with increased incident fracture risk before (hazard ratio = 1.22; CI = 1.13-1.32; P < 0.001) but not after covariate adjustment. Mean (SD) change in femoral neck BMD T-score over 10 years, in those using ACH medications at both years 0 and 5, was -0.60 (0.63) in ACH users versus -0.49 (0.45) in nonusers (P = 0.041), but this was not significant after covariate adjustment. CONCLUSIONS: ACH medications were not found to be independently associated with an increased risk of falling, fractures, or BMD loss. Rather, factors associated with ACH medication use explained the apparent associations.

Fractures are increased and bisphosphonate use decreased in individuals with insulin-dependent diabetes: a 10 year cohort study.

BACKGROUND: Individuals with diabetes have been found previously to be at increased risk of non-traumatic fracture. However, it is unclear if these individuals are being identified and treated for osteoporosis. METHODS: 7753 Canadians over 50 years of age were followed prospectively for 10 years. 606/7753 (7.8%) of had diabetes; 98 were insulin-dependent and 508 were not. Using a cox proportional hazards model, we assessed the association between diabetes status and incident non-traumatic fracture. Using logistic regression we identified factors associated with bisphosphonate use over the 10 year period of study. RESULTS: Mean (SD) age of participants was 66.7(9.4) years and 72% were female. Those with diabetes had higher BMD T-scores at baseline, with a mean (SD) femoral neck T-Score of -0.97 (1.06), compared to -1.24 (0.99) in the general cohort. The adjusted hazard ratio (HR) for incident non-traumatic fracture in individuals with insulin-dependent diabetes over the 10 year study period was 2.50 (95% confidence interval [CI] 1.60, 3.90; p < 0.001). Despite this increased fracture rate, individuals with diabetes (insulin-dependent or non-insulin-dependent) were less likely to be on bisphosphonate therapy at any point over 10 years of prospective follow up compared to other CaMos subjects (odds ratio [OR]: 0.59; 95% CI 0.46-0.75, p < 0.001). CONCLUSIONS: Despite the increased risk of non-traumatic fracture associated with insulin-dependent diabetes, we that found individuals with diabetes are less likely to be treated with a bisphosphonate than those without diabetes. These findings point to a possible care gap in the treatment of non-traumatic fractures in individuals with diabetes in Canada.

Clinical risk factors for fracture in diabetes: a matched cohort analysis.

The objective was to determine which individuals with diabetes are at increased risk for fracture. It is unknown whether traditional clinical risk factors (CRFs) can be used in this population to identify individuals at higher risk of fracture. Using the Manitoba Bone Density Program database, we identified 3054 diabetic women and 9151 matched nondiabetic controls. The independent association of specific CRFs with incident osteoporotic fracture risk was assessed separately in those with diabetes and in controls, with subsequent examination of the interaction between diagnosed diabetes and each CRF. Prior major fractures were more prevalent in the diabetic group compared with the nondiabetic group (16.2% vs 14.3%, p<0.001). During mean 4 yr of observation, 259 (8.5%) of diabetic women and 559 (6.5%) of nondiabetic women experienced an incident major osteoporotic fracture (unadjusted hazard ratio [HR] for diabetes 1.49 [95% confidence interval (CI): 1.28-1.72], p<0.001; adjusted HR 1.14 [95% CI: 1.10-1.18], p<0.001). There were no significant differences between the 2 groups in the HRs for incident fracture associated with any of the CRFs studied (all p-for-interaction >0.1). Diabetes is a risk factor for major fracture. The ability of traditional CRFs to predict osteoporotic fractures is not influenced by the diagnosis of diabetes.

Frequency of bone mineral density testing in adult kidney transplant recipients from Ontario, Canada: a population-based cohort study.

BACKGROUND: We lack consensus on the clinical value, frequency, and timing of bone mineral density (BMD) testing in kidney transplant recipients. This study sought to determine practice patterns in BMD testing across kidney transplant centres in Ontario, Canada, and to compare the frequency of testing in kidney transplant recipients to non-transplant reference groups. METHODS: Using healthcare databases from Ontario, Canada we conducted a population-based cohort study of adult kidney transplant recipients who received a transplant from 1994-2009. We used logistic regression to determine if there was a statistically significant difference across transplant centres in the decision to perform at least one BMD test after transplantation, adjusting for covariates that may influence a physician's decision to order a BMD test. We used the McNemar's test to compare the number of recipients who had at least one BMD test to non-transplant reference groups (matching on age, sex, and date of cohort entry). RESULTS: In the first 3 years after transplant, 4821 kidney transplant recipients underwent 4802 BMD tests (median 1 test per recipient, range 0 to 6 tests), costing $600,000 (2014 CAD equivalent dollars). Across the six centres, the proportion of recipients receiving at least one BMD test varied widely (ranging from 15.6 to 92.1 %; P < 0.001). Over half (58 %) of the recipients received at least one BMD test post-transplant, a value higher than two non-transplant reference groups (general population with a previous non-vertebral fracture [hip, forearm, proximal humerus], 13.8 %; general population with no previous non-vertebral fracture, 8.5 %; P value <0.001 for each of the comparisons). CONCLUSIONS: There is substantial practice variability in BMD testing after transplant. New high-quality information is needed to inform the utility, optimal timing, and frequency of BMD testing in kidney transplant recipients.

MISE EN CONTEXTE: À ce jour, il n'existe aucun consensus sur la pertinence, au plan clinique, de demander une analyse de la densité minérale osseuse (DMO) chez les receveurs d'une greffe de rein, non plus que sur la fréquence ni le moment opportun pour y soumettre les patients après leur intervention. OBJECTIFS DE L'ÉTUDE: L'étude avait pour but d'établir un schéma de pratique pour la mesure de la DMO dans plusieurs centres de transplantation rénale en Ontario, au Canada. On a également voulu comparer la fréquence de ces analyses chez les patients ayant reçu une greffe rénale par rapport à un groupe de référence constitué de patients non transplantés. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude rétrospective par cohorte représentative de la population, qui s'est tenue dans six centres de transplantation rénale en Ontario, au Canada. PATIENTS: Il s'agit d'une cohorte de patients ayant reçu une greffe du rein entre 1994 et 2009. MESURES: Les renseignements sur la fréquence, le coût total et les variations dans le nombre d'analyses de la DMO pour une période couvrant les trois années suivant la greffe ont été compilés dans chacun des six centres. La fréquence des analyses de la DMO chez les patients greffés a été comparée à la fréquence de ces mêmes tests pratiqués chez les sujets de groupes témoins, apparentés sur les plans de l'âge, du sexe et de la date de leur admission dans la cohorte, mais n'ayant pas subi une greffe du rein. MÉTHODE: L'analyse par régression logistique a été utilisée pour établir la présence de différences significatives du point de vue statistique entre les six centres de transplantation en regard de la décision d'effectuer au moins un test de DMO à la suite d'une greffe rénale. L'analyse a tenu compte des covariables qui pouvaient influencer les médecins traitants au moment de décider de procéder ou non à un test de DMO sur leurs patients greffés. Le test McNemar a été utilisé pour comparer le nombre de patients greffés ayant été soumis à une analyse de leur DMO par rapport au groupe témoin. RÉSULTATS: À l'intérieur d'une période de trois ans suivant leur transplantation, un total de 4802 analyses de DMO ont été demandées parmi les 4821 patients greffés du rein répertoriés dans les six centres participant à l'étude. La valeur médiane se situait à un test par patient sur une échelle allant de 0 à 6 tests par patient. Le coût total évalué pour ces 4802 analyses de DMO était de 600 000 CDN en 2014. La proportion de receveurs de greffe ayant été soumis à une analyse de leur DMO a fluctué considérablement d'un centre de transplantation à l'autre, avec des pourcentages variant de 15,6 % à 92,1 % (P < 0,001). Dans l'ensemble, on a analysé la DMO de plus de la moitié (58 %) des patients greffés au moins une fois après leur intervention. Ce résultat s'est avéré plus élevé que les pourcentages mesurés dans deux des groupes témoins non transplantés (valeur de P < 0,001 pour chaque cas) : un premier groupe constitué de gens qui avaient subi une fracture non vertébrale (hanche, avant-bras ou humérus proximal) par le passé (13,8 %) et un second groupe constitué de gens de la population générale n'ayant pas subi de fractures (8,5 %). LIMITES DE L'ÉTUDE: Les renseignements concernant les médicaments d'ordonnance administrés aux participants étaient incomplets et les valeurs de DMO étaient manquantes dans plusieurs cas. De plus, le faible taux de fractures subies par les participants ne permet pas d'établir une relation entre la valeur de DMO mesurée et le risque de fractures. CONCLUSIONS: Une variabilité importante a été constatée dans la pratique d'analyses de la DMO à la suite d'une transplantation rénale. Davantage de données sont nécessaires pour discuter de la pertinence d'effectuer ce test chez les receveurs de greffe rénale, ainsi que pour établir le moment opportun et la fréquence à laquelle les y soumettre après l'intervention.

Risk factors for fracture in adult kidney transplant recipients.

AIM: To determine the general and transplant-specific risk factors for fractures in kidney transplant recipients. METHODS: We conducted a cohort study of all adults who received a kidney-only transplant (n = 2723) in Ontario, Canada between 2002 and 2009. We used multivariable Cox proportional hazards regression to determine general and transplant-specific risk factors for major fractures (proximal humerus, forearm, hip, and clinical vertebral). The final model was established using the backward elimination strategy, selecting risk factors with a P-value ≤ 0.2 and forcing recipient age and sex into the model. We also assessed risk factors for other fracture locations (excluding major fractures, and fractures involving the skull, hands or feet). RESULTS: There were 132 major fractures in the follow-up (8.1 fractures per 1000 person-years). General risk factors associated with a greater risk of major fracture were older recipient age [adjusted hazard ratio (aHR) per 5-year increase 1.11, 95%CI: 1.03-1.19] and female sex (aHR = 1.81, 95%CI: 1.28-2.57). Transplant-specific risk factors associated with a greater risk of fracture included older donor age (5-year increase) (aHR = 1.09, 95%CI: 1.02-1.17) and end-stage renal disease (ESRD) caused by diabetes (aHR = 1.72, 95%CI: 1.09-2.72) or cystic kidney disease (aHR = 1.73, 95%CI: 1.08-2.78) (compared to glomerulonephritis as the reference cause). Risk factors across the two fracture locations were not consistent (major fracture locations vs other). Specifically, general risk factors associated with an increased risk of other fractures were diabetes and a fall with hospitalization prior to transplantation, while length of time on dialysis, and renal vascular disease and other causes of ESRD were the transplant-specific risk factors associated with a greater risk of other fractures. CONCLUSION: Both general and transplant-specific risk factors were associated with a higher risk of fractures in kidney transplant recipients. Results can be used for clinical prognostication.

Fracture Incidence in Adult Kidney Transplant Recipients.

BACKGROUND: It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. METHODS: We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). RESULTS: Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). CONCLUSIONS: Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.

Type 1 diabetes and osteoporosis: from molecular pathways to bone phenotype.

The link between type 1 diabetes mellitus (DM1) and osteoporosis, identified decades ago, has gained attention in recent years. While a number of cellular mechanisms have been postulated to mediate this association, it is now established that defects in osteoblast differentiation and activity are the main culprits underlying bone fragility in DM1. Other contributing factors include an accumulation of advanced glycation end products (AGEs) and the development of diabetes complications (such as neuropathy and hypoglycemia), which cause further decline in bone mineral density (BMD), worsening geometric properties within bone, and increased fall risk. As a result, patients with DM1 have a 6.9-fold increased incidence of hip fracture compared to controls. Despite this increased fracture risk, bone fragility remains an underappreciated complication of DM1 and is not addressed in most diabetes guidelines. There is also a lack of data regarding the efficacy of therapeutic strategies to treat osteoporosis in this patient population. Together, our current understanding of bone fragility in DM1 calls for an update of diabetes guidelines, better screening tools, and further research into the use of therapeutic strategies in this patient population.

Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review.

OBJECTIVE: People with epilepsy (PWE) have an increased fracture risk, independent of seizures. Antiepileptic drugs are thought to increase this risk, particularly those that induce the hepatic cytochrome P450 enzyme system. We aimed to determine whether PWE treated with enzyme-inducing antiepileptic drugs (EIAEDs) have decreased bone mineral density (BMD), or increased fracture incidence, versus those treated with non-EIAEDs. METHODS: We searched MedLine, EMBase, CENTRAL, and CINAHL prior to November 2014 for all studies comparing fracture risk, or BMD change, in PWE treated for ≥ 1 year with EIAEDs versus non-EIAEDs. RESULTS: Thirteen observational studies met eligibility criteria. These studies, representing 68,973 adult PWE, were significantly heterogeneous, making meta-analysis impossible. Study results were split, with 5 studies showing decreased BMD in EIAED users, 5 studies showing no effect of EIAED on BMD, 2 studies showing increased fracture incidence in EIAED users, and 1 study showing no difference in fracture risk. The largest study (n = 63,259), which was also the most methodologically rigorous, showed an increased hazard ratio of 9-22% for any fracture, and 49-53% for hip fracture, in EIAED users. SIGNIFICANCE: The literature is divided regarding the bone effects of EIAEDs; however, current best evidence supports an increased fracture risk in PWE treated with an EIAED compared to those treated with non-EIAEDs. A single article dominated our review, and other large methodologically rigorous studies are needed to confirm or refute its results. Further small studies, with limited power to control for multiple potentially confounding variables, are not likely to help.

The risk of fall and fracture with the initiation of a prostate-selective α antagonist: a population based cohort study.

STUDY QUESTION: Do men starting treatment with prostate-specific α antagonists have increased risk of fall and fracture? METHODS: Administrative datasets from the province of Ontario, Canada, that contain patient level data were used to generate a cohort of 147,084 men aged ≥ 66 years who filled their first outpatient prescription for prostate-specific α antagonists tamsulosin, alfuzosin, or silodosin between June 2003 and December 2013 (exposed men) plus an equal sized cohort matched 1:1 (using a propensity score model) who did not initiate α antagonist therapy. The primary outcome was a hospital emergency room visit or inpatient admission for a fall or fracture in the 90 days after exposure. STUDY ANSWER AND LIMITATIONS: The men exposed to prostate-specific α antagonist had significantly increased risks of falling (odds ratio 1.14 (95% CI 1.07 to 1.21), absolute risk increase 0.17% (0.08 to 0.25%)) and of sustaining a fracture (odds ratio 1.16 (1.04 to 1.29), absolute risk increase 0.06% (0.02 to 0.11%)) compared with the unexposed cohort. This increased risk was not observed in the period before α antagonist use. Secondary outcomes of hypotension and head trauma were also significantly increased in the exposed cohort (odds ratios 1.80 (1.59 to 2.03) and 1.15 (1.04 to 1.27) respectively). The two cohorts were similar across 98 different covariates including demographics, comorbid conditions, medication use, healthcare use, and prior medical investigation. Potential unmeasured confounders, such as physical deconditioning, mobility impairment, and situational risk factors, may exist. The data used to identify the primary outcomes had limited sensitivity, so the absolute risks of the outcomes are probably underestimates. The study only included men ≥ 66 years old, and 84% of exposed men were prescribed tamsulosin, so results may not be generalizable to younger men, and there may not be statistical power to show small differences in outcomes between the drugs. WHAT THIS STUDY ADDS: Prostate-specific α antagonists are associated with a small but significant increased risk of fall, fracture, and head trauma, probably as a result of induced hypotension. FUNDING, COMPETING INTERESTS, DATA SHARING: This project was conducted at the Institute for Clinical Evaluative Sciences (ICES) Western Site through the Kidney, Dialysis, and Transplantation (KDT) research program. BW has received a research grant from Astellas, and L-AF does consultancy for Amgen.

Patterns of use for brand-name versus generic oral bisphosphonate drugs in Ontario over a 13-year period: a descriptive study.

BACKGROUND: Bisphosphonates are the first-line therapy for the treatment of osteoporosis. In the province of Ontario, the Ontario Drug Benefit Program funds medications for patients aged 65 years and older. The Ontario Drug Benefit Program has a generic substitution policy that requires lower-cost generic drugs to be dispensed when they are available. However, there is controversy surrounding the efficacy and tolerability of generic bisphosphonates. The objective of this study was to describe patterns in the use of brand-name versus generic formulations when dispensing oral bisphosphonate over a 13-year period. METHODS: We identified all osteoporotic preparations for alendronate and risedronate that were dispensed through the Ontario Drug Benefit Program from 2001 to 2014. We stratified our sample into community-dwelling residents and residents in long-term care facilities. The number of prescriptions dispensed per month were plotted to illustrate trends over time. RESULTS: We found a rapid switch from brand-name to generic bisphosphonate equivalents immediately after the generic became available on the Ontario Drug Benefit formulary, with generics accounting for > 88% of dispensed drug within 2 months. We also observed a reduction in the number of generic drugs dispensed each time a new brand-name alternative (e.g., monthly risedronate, weekly alendronate plus vitamin D) was introduced to the formulary. The dispensing trends were similar in the community and long-term care settings. INTERPRETATION: The Ontario Drug Benefit Program generic substitution policy resulted in rapid uptake of generic oral bisphosphonates among seniors in Ontario. However, there was a switch away from generic medications to new brand-name alternatives whenever they were introduced to the formulary. Therefore, some patients continued to use brand-name bisphosphonate despite the availability of generic options.

Comparison of fracture risk prediction among individuals with reduced and normal kidney function.

BACKGROUND AND OBJECTIVES: The Fracture Risk Assessment Tool (FRAX) is widely used to predict the 10-year probability of fracture; however, the clinical utility of FRAX in CKD is unknown. This study assessed the predictive ability of FRAX in individuals with reduced kidney function compared with individuals with normal kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The discrimination and calibration (defined as the agreement between observed and predicted values) of FRAX were examined using data from the Canadian Multicentre Osteoporosis Study (CaMos). This study included individuals aged ≥40 years with an eGFR value at year 10 of CaMos (defined as baseline). The cohort was stratified by kidney function at baseline (eGFR<60 ml/min per 1.73 m(2) [72.2% stage 3a, 23.8% stage 3b, and 4.0% stage 4/5] versus ≥60 ml/min per 1.73 m(2)) and followed individuals for a mean of 4.8 years for an incident major osteoporotic fracture (clinical spine, hip, forearm/wrist, or humerus). RESULTS: There were 320 individuals with an eGFR<60 ml/min per 1.73 m(2) and 1787 with an eGFR≥60 ml/min per 1.73 m(2). The mean age was 67±10 years and 71% were women. The 5-year observed major osteoporotic fracture risk was 5.3% (95% confidence interval [95% CI], 3.3% to 8.6%) in individuals with an eGFR<60 ml/min per 1.73 m(2), which was comparable to the FRAX-predicted fracture risk (6.4% with bone mineral density; 8.2% without bone mineral density). A statistically significant difference was not observed in the area under the curve values for FRAX in individuals with an eGFR<60 ml/min per 1.73 m(2) versus ≥60 ml/min per 1.73 m(2) (0.69 [95% CI, 0.54 to 0.83] versus 0.76 [95% CI, 0.70 to 0.82]; P=0.38). CONCLUSIONS: This study showed that FRAX was able to predict major osteoporotic fractures in individuals with reduced kidney function; further study is needed before FRAX should be routinely used in individuals with reduced kidney function.

Build better bones with exercise: protocol for a feasibility study of a multicenter randomized controlled trial of 12 months of home exercise in women with a vertebral fracture.

BACKGROUND: Our goal is to conduct a multicenter randomized controlled trial (RCT) to investigate whether exercise can reduce incident fractures compared with no intervention among women aged ≥65 years with a vertebral fracture. OBJECTIVES: This pilot study will determine the feasibility of recruitment, retention, and adherence for the proposed trial. DESIGN: The proposed RCT will be a pilot feasibility study with 1:1 randomization to exercise or attentional control groups. SETTING: Five Canadian sites (1 community hospital partnered with an academic center and 4 academic hospitals or centers affiliated with an academic center) and 2 Australian centers (1 academic hospital and 1 center for community primary care, geriatric, and rehabilitation services). PARTICIPANTS: One hundred sixty women aged ≥65 years with vertebral fracture at 5 Canadian and 2 Australian centers will be recruited. INTERVENTION: The Build Better Bones With Exercise (B3E) intervention includes exercise and behavioral counseling, delivered by a physical therapist in 6 home visits over 8 months, and monthly calls; participants are to exercise ≥3 times weekly. Controls will receive equal attention. MEASUREMENTS: Primary outcomes will include recruitment, retention, and adherence. Adherence to exercise will be assessed via calendar diary. Secondary outcomes will include physical function (lower extremity strength, mobility, and balance), posture, and falls. Additional secondary outcomes will include quality of life, pain, fall self-efficacy, behavior change variables, intervention cost, fractures, and adverse events. Analyses of feasibility objectives will be descriptive or based on estimates with 95% confidence intervals, where feasibility will be assessed relative to a priori criteria. Differences in secondary outcomes will be evaluated in intention-to-treat analyses via independent Student t tests, chi-square tests, or logistic regression. The Bonferroni method will be used to adjust the level of significance for secondary outcomes so the overall alpha level is .05. LIMITATIONS: No assessment of bone mineral density will be conducted. The proposed definitive trial will require a large sample size. CONCLUSIONS: The viability of a large-scale exercise trial in women with vertebral fractures will be evaluated, as well as the effects of a home exercise program on important secondary outcomes.

Fracture risk associated with continuation versus discontinuation of bisphosphonates after 5 years of therapy in patients with primary osteoporosis: a systematic review and meta-analysis.

PURPOSE: The risks and benefits of continuing bisphosphonate therapy beyond 5 years in patients with primary osteoporosis have not been well established. METHODS: We searched MedLine, EMBase, CENTRAL, CINAHL, and AgeLine prior to February 2010. Bibliographies were also searched and experts in the field contacted. The ProQuest Dissertations and Theses database and relevant conference proceedings were searched to identify unpublished or ongoing studies. Two authors independently reviewed search results. Randomized controlled trials and comparative nonrandomized controlled trials examining post-menopausal women or men ≥50 years of age with primary osteoporosis assigned to continue versus discontinue bisphosphonate therapy after ≥5 years of therapy were included. Of 1188 identified articles, three studies (n = 1443) met criteria for inclusion in data synthesis. Data were extracted and risk of bias assessed by two independent reviewers using predefined criteria. RESULTS: No statistically significant association was found between fracture incidence and the discontinuation of therapy beyond 5 years for any type of fracture: clinical nonvertebral fracture (relative risk [RR] = 0.97; 95% confidence interval [CI] 0.77-1.23), clinical vertebral fracture (RR = 0.61; 95% CI 0.32-1.19), or morphometric vertebral fracture (RR = 0.90; 95% CI 0.5-1.64). No differences in adverse events were identified between the two groups. CONCLUSION: We found no significant difference in fracture risk or adverse events between postmenopausal women with primary osteoporosis who continued bisphosphonate therapy versus those who discontinued bisphosphonate therapy after 5 years of treatment. However, given the small number and limited quality of available studies, no firm conclusions or recommendations can be made.

Validity of the primary care diagnosis of diabetes in veterans in the southeastern United States.

AIMS: To determine the validity of diagnosis of diabetes in primary care. METHODS: Patients with initial primary care diagnosis (ICD-9 code 250.xx) were compared to matched controls (without code or diabetes drugs), and patients meeting VA Diabetes Epidemiology Cohort (DEpiC) criteria (any 250.xx twice, or diabetes drug) in "diagnostic accuracy" (whether hyperglycemia preceded diagnosis) and "predictive accuracy" (whether diabetes drug or A1c ≥ 6.5% followed diagnosis). RESULTS: Only 1.8% of primary care diagnoses met ADA criteria, while nonstandard non-fasting morning glucose ≥ 126 mg/dl or A1c ≥ 6.5% were utilized in 51.5%; broad "diagnostic accuracy" criteria were met in 53% of 2980 primary care vs. 2% of 13,397 control (p<0.001), and 60% of 2456 DEpiC patients (p<0.001). "Predictive accuracy" was 88% in primary care diagnosis vs. 12% control (p<0.001) and 93% DEpiC patients (p=0.08), but was higher if ADA criteria were met. Delay from hyperglycemia to diagnosis averaged 12.5 months in primary care vs. 20.1 months in DEpiC patients (p<0.001). CONCLUSIONS: While generally not based on ADA criteria, the primary care diagnosis of diabetes is valid, and identifies patients earlier than detection by DEpiC criteria. Either primary care diagnosis or DEpiC criteria could be used to trigger electronic reminders aimed to facilitate management.

Risk factors for idiopathic intracranial hypertension in men: a case-control study.

OBJECTIVE: To identify risk factors for idiopathic intracranial hypertension (IIH) in men. DESIGN: Case-control study. A 96-item telephone questionnaire, answered retrospectively, with cases recalling at the age of their diagnosis and controls recalling at the age of their corresponding case's diagnosis. SETTING: Outpatient clinics in two US tertiary care centers. PARTICIPANTS: The characteristics of 24 men with IIH were compared to those of 48 controls matched for sex, age, race, and World Health Organization body mass index (BMI) category. MAIN OUTCOME MEASURES: Two previously validated questionnaires: the ADAM (Androgen Deficiency in Aging Males) questionnaire for testosterone deficiency and the Berlin questionnaire for obstructive sleep apnea (OSA), embedded within the telephone questionnaire. Analysis with Mantel-Haenszel odds ratios and mixed-effects logistic regression models accounted for matching. RESULTS: Cases and controls had similar enrollment matching characteristics. Although matching was successful by BMI category, there was a small difference between BMI values of cases and controls (cases: median 31.7, controls: median 29.9; p=0.03). After adjustment by BMI value, men with IIH were significantly more likely than controls to have a positive ADAM questionnaire for testosterone deficiency (OR: 17.4, 95% CI: 5.6-54.5; p<0.001) and significantly more likely to have either a positive Berlin questionnaire for OSA or history of diagnosed OSA (OR: 4.4, 95% CI: 1.5-12.9; p=0.03). CONCLUSIONS: Men with IIH are more likely than controls to have symptoms associated with testosterone deficiency and OSA. These associations suggest a possible role for sex hormones and OSA in the pathogenesis of IIH in men.