Breastfeeding protects against hip fracture in postmenopausal women: The Tromsø study

Despite reported bone loss during pregnancy and lactation, no study has shown deleterious long‐term effects of parity or breastfeeding. Studies have shown higher bone mineral density and reduced risk for fracture in parous than in nulliparous women or no effect of parity and breastfeeding, so long‐term effects are uncertain. We studied the effect of parity and breastfeeding on risk for hip, wrist and non‐vertebral fragility fractures (hip, wrist, or proximal humerus) in 4681 postmenopausal women aged 50 to 94 years in the Tromsø Study from 1994–95 to 2010, using Cox's proportional hazard models. During 51 906 person‐years, and a median of 14.5 years follow‐up, 442, 621, and 1105 of 4681 women suffered incident hip, wrist, and fragility fractures, and the fracture rates were 7.8, 11.4, and 21.3 per 1000 person‐years, respectively. The risk for hip, wrist, and fragility fracture did not differ between parous (n = 4230, 90.4%) and nulliparous women (n = 451, 9.6%). Compared with women who did not breast‐feed after birth (n = 184, 4.9%), those who breastfed (n = 3564, 95.1%) had 50% lower risk for hip fracture (HR 0.50; 95% CI 0.32 to 0.78), and 27% lower risk for fragility fracture (HR 0.73; 95% CI 0.54 to 0.99), but similar risk for wrist fracture, after adjustment for age, BMI, height, physical activity, smoking, a history of diabetes, previous fracture of hip or wrist, use of hormone replacement therapy, and length of education. Each 10 months longer total duration of breastfeeding reduced the age‐adjusted risk for hip fracture by 12% (HR 0.88; 95% CI 0.78 to 0.99, p for trend = 0.03) before, and marginally after, adjustment for BMI and other covariates (HR 0.91; 95% CI 0.80 to 1.04). In conclusion, this data indicates that pregnancy and breastfeeding has no long‐term deleterious effect on bone fragility and fractures, and that breastfeeding may contribute to a reduced risk for hip fracture after menopause. © 2011 American Society for Bone and Mineral Research     

Long‐Term Randomized Trial of Intensive Versus Symptomatic Management in Paget's Disease of Bone: The PRISM‐EZ Study

It has been suggested that normalization of bone turnover may improve clinical outcome in Paget's disease of bone (PDB) by preventing complications such as fractures and the development of osteoarthritis. Here we investigated the long‐term effects of a treatment strategy that aimed to normalize bone turnover in PDB with that of symptomatic treatment. The study group comprised 502 subjects who were enrolled into a 3‐year extension of the Paget's Disease: Randomized Trial of Intensive versus Symptomatic Management (PRISM) study. Intensive bisphosphonate therapy was continued in 270 of these subjects with the aim of normalizing bone turnover using zoledronic acid as the treatment of first choice. Symptomatic treatment continued in 232 subjects in whom bisphosphonates were only given for the treatment of bone pain. The primary outcome was fracture and secondary outcomes were orthopedic procedures, quality of life, and bone pain, adjusted for baseline characteristics. Serum total alkaline phosphatase (ALP) concentrations were significantly lower in the intensive group on entry to the study and the differences between groups increased as the study progressed. There were no clinically important differences in quality of life measures or bone pain between the treatment groups. Intensive treatment was associated with a nonsignificant increase in fracture risk (hazard ratio = 1.90; 95% CI, 0.91 to 3.98; p = 0.087), orthopedic procedures (1.81; 95% CI, 0.71 to 4.61; p = 0.214), and serious adverse events (relative risk 1.28; 95% CI, 0.96 to 1.42). We conclude that long‐term intensive bisphosphonate therapy confers no clinical benefit over symptomatic therapy and is associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. The results of this study suggest that in patients with established PDB, bisphosphonate therapy should focus on control of symptoms rather than suppression of bone turnover. © 2016 American Society for Bone and Mineral Research.     

The Impact of Acute Kidney Injury With Temporary Dialysis on the Risk of Fracture

Acute kidney injury (AKI) has a negative impact on long‐term renal function and prognosis. However, the association between acute renal dysfunction and long‐term effects on bone disorders has not yet been characterized. Using a population‐based cohort study, we aimed to evaluate associations between AKI and long‐term effects on bone fractures. We identified relevant data of all hospitalized patients aged >18 years with histories of dialysis‐requiring AKI, with subsequent recovery and discharge, from the claim records of the Taiwan National Health Insurance database between 2000 and 2008. We determined long‐term de novo bone fracture and all‐cause mortality after patients' index‐hospitalization discharge using propensity score–adjusted Cox proportional hazard model. Varying‐time models were used to adjust for long‐term effects of end‐stage renal disease (ESRD) on main outcomes. Among 448 AKI patients who had dialysis and survived 90 days after index‐hospitalization discharge without reentering dialysis, 273 were male (60.9%) with a mean age of 61.4 ± 16.6 years. Controls included 1792 hospitalized patients without AKI, dialysis, or bone fracture history. In the AKI recovery group, bone fracture incidence was 320 per 10,000 person‐years and hazard ratio (HR) of long‐term bone fracture was 1.25 (p = 0.049) compared with the control group, independent of subsequent ESRD status (HR = 1.55; p = 0.01). Both AKI recovery status (HR = 2.31; p < 0.001) and time varying factor of bone fracture (HR = 1.43; p < 0.001) were independent predictors of mortality compared with controls. In conclusion, AKI requiring temporary dialysis independently increases long‐term risk of bone fracture, regardless of subsequent progression to ESRD. Long‐term bone fractures may negatively impact patient mortality. © 2014 American Society for Bone and Mineral Research.     

The Relationship Between Proton Pump Inhibitor Adherence and Fracture Risk in the Elderly

Studies suggest that long-term use of proton pump inhibitors (PPIs) may be associated with an increased risk of fracture. However, the role of medication adherence in this association is not fully understood. A retrospective cohort study was conducted to examine the relationship between PPI use/adherence and fracture risk among elderly subjects by combining administrative pharmacy claims data, survey data, and Medicare data. The study cohort included 1,604 PPI users and 23,672 nonusers who were enrolled in Pennsylvania’s Pharmaceutical Assistance Contract for the Elderly program. PPI adherence was measured by the proportion of days covered (PDC). Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) of PPI use/adherence for fracture risk while controlling for demographics, comorbidity, body mass index, smoking, and non-PPI medication use. The overall incidence of any fracture per 100 person-years was 8.7 for PPI users and 5.0 for nonusers. A gradient in fracture risk according to PPI adherence was observed. Relative to nonusers, fracture HRs associated with the highest (PDC ≥ 0.80), intermediate (PDC 0.40–0.79), and lowest (PDC <0.40) adherence levels were 1.46 (p < 0.0001), 1.30 (p = 0.02), and 0.95 (p = 0.75), respectively. In addition, the fracture risk of PPI use was significant for hip (HR = 1.32, p = 0.04) and vertebral (HR = 1.69, p = 0.0005) fractures, and risk was similar between major osteoporotic and other fractures. These results provide further evidence that PPI use may increase fracture risk in the elderly and highlight the need for clinicians to periodically reassess elderly patients’ individualized needs for ongoing PPI therapy, while weighing potential risks and benefits.     

High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures: The MrOS Sweden Study

Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population‐based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 μg/L compared with 159.4 μg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10‐year follow‐up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03–1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04–1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31–4.02) for hip fracture and 1.82 (95% CI 1.17–2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03–2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26–2.87). Serotonin was positively associated with hand‐grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = ?0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person‐years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures. © 2018 American Society for Bone and Mineral Research.     

Mild hyponatremia as a risk factor for fractures: The rotterdam study

Recent studies suggest that mild hyponatremia is associated with fractures, but prospective studies are lacking. We studied whether hyponatremia is associated with fractures, falls, and/or bone mineral density (BMD). A total of 5208 elderly subjects with serum sodium assessed at baseline were included from the prospective population‐based Rotterdam Study. The following data were analyzed: BMD, vertebral fractures (mean follow‐up 6.4 years), nonvertebral fractures (7.4 years), recent falls, comorbidity, medication, and mortality. Hyponatremia was detected in 399 subjects (7.7%, 133.4 ± 2.0 mmol/L). Subjects with hyponatremia were older (73.5 ± 10.3 years versus 70.0 ± 9.0 years, p < .001), had more recent falls (23.8% versus16.4%, p < .01), higher type 2 diabetes mellitus prevalence (22.2% versus 10.3%, p < .001), and more often used diuretics (31.1% versus 15.0%, p < .001). Hyponatremia was not associated with lower BMD but was associated with increased risk of incident nonvertebral fractures [hazard ratio (HR) =1.39, 95% confidence interval (CI) 1.11–1.73, p = .004] after adjustment for age, sex, and body mass index. Further adjustments for disability index, use of diuretics, use of psycholeptics, recent falls, and diabetes did not modify results. In the fully adjusted model, subjects with hyponatremia also had increased risk of vertebral fractures at baseline [odds ratio (OR) = 1.78, 95% CI 1.04–3.06, p = .037] but not at follow‐up. Finally, all‐cause mortality was higher in subjects with hyponatremia (HR = 1.21, 95% CI 1.03–1.43, p = .022). It is concluded that mild hyponatremia in the elderly is associated with an increased risk of vertebral fractures and incident nonvertebral fractures but not with BMD. Increased fracture risk in hyponatremia also was independent of recent falls, pointing toward a possible effect on bone quality. © 2011 American Society for Bone and Mineral Research     

Optimism,Cynical Hostility,Falls, and Fractures: The Women's Health Initiative Observational Study (WHI‐OS)

Traits of optimism and cynical hostility are features of personality that could influence the risk of falls and fractures by influencing risk‐taking behaviors, health behaviors, or inflammation. To test the hypothesis that personality influences falls and fracture risk, we studied 87,342 women enrolled in WHI‐OS. Optimism was assessed by the Life Orientation Test–Revised and cynical hostility, the cynicism subscale of the Cook‐Medley questionnaire. Higher scores indicate greater optimism and hostility. Optimism and hostility were correlated at r = –0. 31, p < 0.001. Annual self‐report of falling ≥2 times in the past year was modeled using repeated measures logistic regression. Cox proportional hazards models were used for the fracture outcomes. We examined the risk of falls and fractures across the quartiles (Q) of optimism and hostility with tests for trends; Q1 formed the referent group. The average follow‐up for fractures was 11.4 years and for falls was 7.6 years. In multivariable (MV)‐adjusted models, women with the highest optimism scores (Q4) were 11% less likely to report ≥2 falls in the past year (odds ratio [OR] = 0.89; 95% confidence intervals [CI] 0.85–0.90). Women in Q4 for hostility had a 12% higher risk of ≥2 falls (OR = 1.12; 95% CI 1.07–1.17). Higher optimism scores were also associated with a 10% lower risk of fractures, but this association was attenuated in MV models. Women with the greatest hostility (Q4) had a modest increased risk of any fracture (MV‐adjusted hazard ratio = 1. 05; 95% CI 1.01–1.09), but there was no association with specific fracture sites. In conclusion, optimism was independently associated with a decreased risk of ≥2 falls, and hostility with an increased risk of ≥2 falls, independent of traditional risk factors. The magnitude of the association was similar to aging 5 years. Whether interventions aimed at attitudes could reduce fall risks remains to be determined. © 2016 American Society for Bone and Mineral Research.     

Physical activity slows femoral bone loss but promotes wrist fractures in postmenopausal women: A 15‐year follow‐up of the OSTPRE study

Results on fracture risk among physically active persons are contradictory. The aim of this study was to investigate the long‐term association between the self‐reported physical activity (PA), the risk of fractures, and bone loss among peri‐ and postmenopausal women. The association between PA and fracture risk was examined during 15 years of follow‐up in the population‐based Osteoporosis Risk Factor and Prevention (OSTPRE) Study among 8560 women with a mean age of 52.2 years (range 47 to 56 years) at baseline. The amount and type of PA, as well as the types and mechanisms of fractures, were registered with self‐administered questionnaires at 5‐year intervals (ie, 1989, 1994, 1999, and 2004). A total of 2641 follow‐up fractures were verified in 2073 women (24.2%). The study cohort was divided into quartiles by average hours of reported PA during the whole follow‐up. Areal bone mineral density (aBMD) at the proximal femur (n = 2050) and lumbar spine (L₂–L₄; n = 1417) was followed at 5‐year intervals from a random stratified subsample with dual X‐ray absorptiometry (DXA). Risk of fracture was estimated by using the Cox proportional hazards model with a mean follow‐up time of 15.2 years. Weekly average time spent on leisure‐time PA was 0.4, 1.7, 3.3, and 7.0 hours from the least to the most active quartiles, respectively. The risk of wrist fracture was higher in the active quartiles (II to IV) than in the most inactive quartile (I), with hazard ratios (HRs) of 1.3 [95% confidence interval (CI) 1.05–1.57, p = .014] for the second (II), 1.2 (95% CI 1.01–1.51, p = .045) for the third (III), and 1.4 (95% CI 1.14–1.69, p = .001) for the fourth (IV) quartile, respectively. Overall, most of the fractures were reported as a result of a fall (69.0%), with a 2.1 times higher rate of wrist fractures during the winter (November to April) than during summer season. There were no significant associations of PA with any other fracture types. Bone loss at the femoral neck, trochanter, and Ward's triangle was significantly associated with long‐term PA (ANCOVA p < .05), whereas no associations of bone loss and PA in lumbar spine were seen. PA is associated with a moderate rise in wrist fracture risk, which might be explained in part by a higher number of outdoor activities. Regular PA of at least 1½ hours per week does not seem to increase the risk of other fractures and might significantly decrease proximal femur bone loss among peri‐ and postmenopausal women. © 2010 American Society for Bone and Mineral Research.     

Circulating Lipocalin 2 Levels Predict Fracture‐Related Hospitalizations in Elderly Women: A Prospective Cohort Study

Lipocalin 2 (LCN2) or neutrophil gelatinase–associated lipocalin (NGAL) is expressed in a wide range of cells and pathological states. Mounting evidence suggests lipocalin 2 may be an important regulator of bone homeostasis. Recently it has been suggested LCN2 is a novel mechanoresponsive gene central to the pathological response to low mechanical force. We undertook a prospective study of 1009 elderly women over 70 years of age to study the association between circulating LCN2 and potential associated variables, including estimated glomerular filtration rate, physical activity, and baseline measures of hip bone density and heel bone quality. Osteoporotic fractures requiring hospitalizations were identified from the Western Australian Data Linkage System. Over 14.5 years, 272 (27%) of women sustained an osteoporotic fracture‐related hospitalization; of these, 101 were hip fractures. Circulating LCN2 levels were correlated with body mass index and estimated glomerular filtration rate (r = 0.249, p < 0.001 and r = –0.481, p < 0.001, respectively) that modified the association with hip and heel bone measures. Per standard deviation increase in LCN2, there was a 30% multivariable‐adjusted increase in the risk of any osteoporotic fracture (hazard ratio [HR] = 1.30, 95% confidence interval [CI] 1.13–1.50, p < 0.001). In participants with elevated LCN2 levels above the median (76.6 ng/mL), there was an 80% to 81% increase in the risk of any osteoporotic or hip fracture (HR = 1.81, 95% CI 1.38–2.36, p < 0.001 and HR = 1.80, 95% CI 1.16–2.78, p = 0.008, respectively). These associations remained significant after adjustment for total hip bone mineral density (p < 0.05). In conclusion, we have demonstrated that circulating LCN2 levels predict future risk of osteoporotic fractures requiring hospitalization. Measurement of LCN2 levels may improve fracture prediction in addition to current fracture risk factors in the elderly, particularly in those with impaired renal function. © 2015 American Society for Bone and Mineral Research.     

Lower fracture risk in older men with higher sclerostin concentration: A prospective analysis from the MINOS study

Sclerostin is synthesized by osteocytes and inhibits bone formation. We measured serum sclerostin levels in 710 men aged 50 years and older. Bone mineral density (BMD) was measured at the lumbar spine, hip, and distal forearm. Serum sclerostin increased with age (unadjusted r = 0.30, p < 0.001). After adjustment for age, weight, and bioavailable 17β‐estradiol, serum sclerostin correlated positively with BMD (r = 0.24 to 0.35, p < 0.001) and negatively with the levels of bone turnover markers (r = ? 0.09 to ? 0.23, p < 0.05 to 0.001). During a 10‐year follow‐up, 75 men sustained fragility fractures. Fracture risk was lower in the two upper quintiles of sclerostin combined versus three lower quintiles combined (6.1 versus 13.5%, p < 0.01). We compared fracture risk in the two highest quintiles combined versus three lower quintiles combined using the Cox model adjusted for age, weight, leisure physical activity, BMD, bone width (tubular bones), prevalent fracture, prevalent falls, ischemic heart disease, and severe abdominal aortic calcification. Men with higher sclerostin concentration had lower fracture risk (adjusted for hip BMD, hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.31 to 0.96, p < 0.05). The results were similar in 47 men with major fragility fractures (adjusted for lumbar spine BMD: HR = 0.39, 95% CI 0.17 to 0.90, p < 0.05). Men who had higher sclerostin and higher BMD (two highest quintiles) had lower risk of fracture compared with men who had lower BMD and lower sclerostin levels (three lower quintiles) (HR = 0.24, 95% CI 0.10 to 0.62, p < 0.005). Circulating sclerostin was not associated with mortality rate or the incidence of major cardiovascular events. Thus, in older men, higher serum sclerostin levels are associated with lower risk of fracture, higher BMD, and lower bone turnover rate. © 2013 American Society for Bone and Mineral Research.     

Risk of Fracture in Primary Aldosteronism: A Population‐Based Cohort Study

Primary aldosteronism (PA) is associated with increased urinary calcium excretion and osteoporosis prevalence. We studied the long‐term effect of hyperaldosterone on fracture risk and possible risk mitigation via treatments, by comparing PA patients and their essential hypertension (EH) counterparts extracted by propensity score match. We used a longitudinal population database from the Taiwan National Health Insurance, and used a validated algorithm to identify PA patients diagnosed in 1997–2010. Our sample included 2533 PA patients, including 921 patients with aldosterone‐producing adenoma (APA). Our methods for assessing excessive fracture risk included multivariable Cox regression and the competing risk regression. The incidence rate of fracture at any site was 14.4 per 1000 person‐years for PA, and 11.2 per 1000 person‐years for APA. In contrast, the incidence rate of fracture at any site was 8.3 per 1000 person‐years in EH controls for PA, and 6.5 per 1000 person‐years in EH controls for APA. Mineralocorticoid receptor antagonist (MRA) treatment might be associated with higher risk of osteoporotic fracture in the whole female PA cohort (subdistribution hazard ratio [SHR] = 2.12, p = 0.008) as well as female APA patients (SHR = 1.15, p = 0.049). As to fracture at any site, MRA treatment was also associated with higher risk; the SHR was 1.88 (p < 0.001) in the whole female PA cohort, and 2.17 (p = 0.019) in female APA patients. PA is tightly associated with higher risk of bone fracture, even in the case where the competing risk of death was controlled. Particularly, female PA patients treated with MRA were confronted with significantly higher risk in bone fracture than their EH controls. © 2017 American Society for Bone and Mineral Research.     

Relationship of Blood Lead Levels to Incident Nonspine Fractures and Falls in Older Women: The Study of Osteoporotic Fractures

Lead is stored in the skeleton and can serve as an endogenous source for many years. Lead may influence the risk of fracture, through direct effects on bone strength or indirectly by disturbing neuromuscular function and increasing the risk of falls. The objective of this analysis is to test the hypothesis that women with higher blood lead levels experience higher rates of falls and fracture. This was a prospective cohort study of 533 women 65–87 yr of age enrolled in the Study of Osteoporotic Fractures at two U.S. research centers (Baltimore, MD; Monongahela Valley, PA) from 1986 to 1988. Blood lead levels (in μg/dl) were measured in 1990–1991 by atomic absorption spectrophotometry and classified as “low” (≤3; lower 15th percentile, referent); “medium” (4–7); or “high” (≥8; upper 15th percentile). Total hip BMD was measured by DXA twice, 3.55 yr apart. Information on falls was collected every 4 mo for 4 yr. Incident nonspine fractures were identified and confirmed over 10 yr. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% CI of fracture. Generalized estimating equations were used to calculate the incident rate ratio of falls (95% CI). The mean blood lead level was 5.3 ± 2.3 (SD) μg/dl (range, 1–21 μg/dl). Baseline BMD was 7% lower in total hip and 5% lower in femoral neck in the highest compared with lowest blood lead group (p < 0.02). Hip bone loss tended to be greater in the high lead group, but differences were not significant. In multivariable adjusted models, women with high blood lead levels had an increased risk of nonspine fracture (HR = 2.50; 95% CI = 1.25, 5.03; p trend = 0.016) and higher risk of falls (incident rate ratio = 1.62; 95% CI = 1.07, 2.45; p trend = 0.014) compared with women with lowest lead level. Blood lead levels are associated with an increased risk of falls and fractures, extending the negative health consequences of lead to include osteoporotic fractures.     

Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study

Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN‐BMD) (n = 765); (2) 4‐year change in FN‐BMD (n = 556); and (3) hip fracture risk (n = 765) over 17‐year follow‐up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN‐BMD over 4 years in women (p‐trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN‐BMD in women (p‐trend = 0.02), and increased hip fracture risk in women and men (p‐trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p‐trend = 0.12 and p‐trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN‐BMD in men (p‐trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN‐BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk. © 2012 American Society for Bone and Mineral Research.     

Antiepileptic drug use,falls, fractures,and BMD in postmenopausal women: Findings from the women's health initiative (WHI)

Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow‐up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30–1.61], all site‐specific fractures including the hip (HR = 1.51, 95% CI 1.05–2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20–2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11–1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29–1.65) and two or more falls (HR = 1.62, 95% CI 1.50–1.74) but not with baseline BMD or changes in BMD (p ≥ .064 for all sites). Use of more than one and use of enzyme‐inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15–2.09 and HR = 1.36, 95% CI 1.09–1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women. © 2010 American Society for Bone and Mineral Research.     

Subtrochanteric and Diaphyseal Femur Fractures in Patients Treated With Alendronate: A Register‐Based National Cohort Study

Alendronate (aln) is a potent bisphosphonate with a prolonged duration of action. Recent reports have found long‐term aln use to be common in patients with subtrochanteric or proximal diaphyseal femur fracture, raising concerns that these fractures could be a consequence of excessive suppression of bone turnover. Two national observational register‐based studies were performed: (1) cross‐sectional study (N = 11,944) comparing age distribution, exposure, and trauma mechanisms between different types of proximal femur fractures and (2) matched cohort study in patients with prior nonhip fractures (N = 5187 + 10,374), testing the hypothesis that the increase in the risk of subsequent atypical femur fractures exceeded the increase in typical hip fractures. We also sought evidence of a dose‐response relationship, where high adherence to or long‐term use of aln led to more atypical femur fractures. We found that 7% of patients with atypical fractures were aln exposed, and the same was found for typical hip fractures. In the cohort study, the HR for subtrochanteric/diaphyseal fracture with aln was 1.46 (0.91–2.35, p = 0·12) compared with 1.45 (1.21–1.74, p < 0·001) for hip fracture after adjustment for comorbidity and co‐medications. The risk was reduced by high adherence, and the ratio between hip and subtrochanteric/diaphyseal femur fractures was identical in aln‐treated patients and the control cohort even in the limited number of patients who received long‐term treatment. Subtrochanteric/diaphyseal femur fractures share the epidemiology and treatment response of classical hip fractures and are best classified as osteoporotic fractures.     

Men with metabolic syndrome have lower bone mineral density but lower fracture risk—the MINOS study

Data on the association of the metabolic syndrome (MetS) with bone mineral density (BMD) and fracture risk in men are inconsistent. We studied the association between MetS and bone status in 762 older men followed up for 10 years. After adjustment for age, body mass index, height, physical activity, smoking, alcohol intake, and serum 25‐hydroxycholecalciferol D and 17β‐estradiol levels, men with MetS had lower BMD at the hip, whole body, and distal forearm (2.2% to 3.2%, 0.24 to 0.27 SD, p < .05 to .005). This difference was related to abdominal obesity (assessed by waist circumference, waist‐hip ratio, or central fat mass) but not other MetS components. Men with MetS had lower bone mineral content (3.1% to 4.5%, 0.22 to 0.29 SD, p < .05 to 0.001), whereas differences in bone size were milder. Men with MetS had a lower incidence of vertebral and peripheral fractures (6.7% versus 12.0%, p < .05). After adjustment for confounders, MetS was associated with a lower fracture incidence [odds ratio (OR) = 0.33, 95% confidence interval (CI) 0.15–0.76, p < .01]. Among the MetS components, hypertriglyceridemia was most predictive of the lower fracture risk (OR = 0.25, 95%CI 0.10–0.62, p < .005). Lower fracture risk in men with MetS cannot be explained by differences in bone size, rate of bone turnover rate and bone loss, or history of falls or fractures. Thus older men with MetS have a lower BMD related to the abdominal obesity and a lower risk of fracture related to hypertriglyceridemia. MetS probably is not a meaningful concept in the context of bone metabolism. Analysis of its association with bone‐related variables may obscure the pathophysiologic links of its components with bone status. © 2010 American Society for Bone and Mineral Research     

Prediction of new clinical vertebral fractures in elderly men using finite element analysis of CT scans

Vertebral strength, as estimated by finite element analysis of computed tomography (CT) scans, has not yet been compared against areal bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) for prospectively assessing the risk of new clinical vertebral fractures. To do so, we conducted a case‐cohort analysis of 306 men aged 65 years and older, which included 63 men who developed new clinically‐identified vertebral fractures and 243 men who did not, all observed over an average of 6.5 years. Nonlinear finite element analysis was performed on the baseline CT scans, blinded to fracture status, to estimate L1 vertebral compressive strength and a load‐to‐strength ratio. Volumetric BMD by quantitative CT and areal BMD by DXA were also evaluated. We found that, for the risk of new clinical vertebral fracture, the age‐adjusted hazard ratio per standard deviation change for areal BMD (3.2; 95% confidence interval [CI], 2.0–5.2) was significantly lower (p < 0.005) than for strength (7.2; 95% CI, 3.6–14.1), numerically lower than for volumetric BMD (5.7; 95% CI, 3.1–10.3), and similar for the load‐to‐strength ratio (3.0; 95% CI, 2.1–4.3). After also adjusting for race, body mass index (BMI), clinical center, and areal BMD, all these hazard ratios remained highly statistically significant, particularly those for strength (8.5; 95% CI, 3.6–20.1) and volumetric BMD (9.4; 95% CI, 4.1–21.6). The area‐under‐the‐curve for areal BMD (AUC = 0.76) was significantly lower than for strength (AUC = 0.83, p = 0.02), volumetric BMD (AUC = 0.82, p = 0.05), and the load‐to‐strength ratio (AUC = 0.82, p = 0.05). We conclude that, compared to areal BMD by DXA, vertebral compressive strength and volumetric BMD consistently improved vertebral fracture risk assessment in this cohort of elderly men. © 2012 American Society for Bone and Mineral Research.     

Bone Mineral Density and Parathyroid Hormone as Independent Risk Factors for Mortality in Community‐Dwelling Older Adults: A Population‐Based Prospective Cohort Study in Brazil. The São Paulo Ageing & Health (SPAH) Study

Previous studies have shown a relationship between osteoporosis and increased mortality risk. However, none of these studies performed a concomitant evaluation of the parathyroid hormone (PTH)‐calcium‐vitamin D axis and bone mass to accurately determine the contribution of each of these parameters to survival in older subjects. Thus, we sought to investigate the association between bone parameters and mortality in a longitudinal, prospective, population‐based cohort of 839 elderly subjects. Clinical data (including history of fractures and cardiovascular events) were assessed using a specific questionnaire. Laboratory exams, including serum 25OHD and PTH, were also performed. Bone mineral density (BMD) at the lumbar spine and hip were evaluated using DXA. All analyses were performed at baseline (2005 to 2007). Mortality was recorded during follow‐up. Multivariate Cox proportional regression was used to compute hazard ratios for all‐cause and cardiovascular mortality. Over a mean 4.06 ± 1.07 years, there were 132 (15.7%) deaths. These individuals were compared to 707 subjects who were alive at the end of the coverage period for mortality data collection. In a multivariate Cox proportional hazards model, age (HR 1.32; 95% CI, 1.13 to 1.55; p = 0.001, for each 5‐year increase), male gender (HR 1.90; 95% CI, 1.30 to 2.79; p = 0.001), recurrent falls (more than two in the previous year; HR 1.65; 95% CI, 1.06 to 2.56; p = 0.026), diabetes mellitus (HR 2.17; 95% CI, 1.46 to 3.21; p < 0.001), low physical activity score (HR 1.78; 95% CI, 1.14 to 2.79; p = 0.011), prior cardiovascular event (HR 1.76; 95% CI, 1.18 to 2.63; p = 0.006), total hip BMD (HR 1.41; 95% CI, 1.15 to 1.72; p = 0.001, per each 1 SD decrease), and intact PTH (iPTH) (HR 1.06; 95% CI, 1.04 to 1.08; p < 0.001, per each 10 pg/mL increase) were independently associated with all‐cause mortality. The subjects in the highest quartile of PTH (>49 pg/mL) were at a higher risk of cardiovascular death (HR 3.09; 95% CI, 1.36 to 6.99; p = 0.007) compared with the subjects in the lowest quartile (<26 pg/mL). Low BMD and higher PTH were significantly associated with mortality in community‐dwelling older adults. These findings support the notion that careful screening of these bone parameters might lead to better management of older patients and improve outcomes in this population. © 2016 American Society for Bone and Mineral Research.     

Risk factors for prediction of inadequate response to antiresorptives

Some patients sustain fractures while on antiresorptives. Whether this represents an inadequate response (IR) to treatment or a chance event has not been elucidated. We performed a study to identify which patients are more likely to fracture while on treatment. This is a multicentric, cross‐sectional study of postmenopausal women on antiresorptives for osteoporosis in 12 Spanish hospitals, classified as adequate responders (ARs) if on treatment with antiresorptives for 5 years with no incident fractures or inadequate responders (IRs) if an incident fracture occurred between 1 and 5 years on treatment. Poor compliance, secondary osteoporosis, and previous anti‐osteoporosis treatment other than the assessed were exclusion criteria. Clinical, demographic, analytical, dual‐energy X‐ray absorptiometry (DXA) variables, and proximal femur structure analysis (ImaTx?) and structural/fractal analyses of distal radius were performed. A total of 179 women (76 IRs; mean (SD): age 68.2 (9.0) years; 103 ARs, age 68.5 (7.9) years) were included. History of prior fracture (p = 0.005), two or more falls in the previous year (p = 0.032), low lumbar spine bone mineral density (BMD) (p = 0.02), 25 hydroxyvitamin D (p = 0.017), and hip ImaTx fracture load index (p = 0.004) were associated with IR. In the logistic regression models a fracture before treatment (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.47–8.82; p = 0.005) and levels of 25 hydroxyvitamin D below 20 ng/mL (OR, 3.89; 95% CI, 1.55–9.77; p = 0.004) significantly increased risk for IR, while increased ImaTx fracture load (OR, 0.96; 95% CI, 0.93–0.99; p = 0.006; per every 100 units) was protective, although the latter became not significant when all three variables were fitted into the model. Therefore, we can infer that severity of the disease, with microarchitectural and structure deterioration, as shown by previous fracture and hip analysis, and low levels of 25 hydroxy vitamin D carry higher risk of inadequate response to antiresorptives. More potent regimes should be developed and adequate supplementation implemented to solve this problem. © 2012 American Society for Bone and Mineral Research.     

Use of DXA‐based finite element analysis of the proximal femur in a longitudinal study of hip fracture

Bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) is used for clinical assessment of fracture risk; however, measurements that incorporate bone strength could improve predictive ability. The aim of this study was to determine whether bone strength derived from finite element (FE) analysis was associated with hip fracture risk in a longitudinal study. We studied 728 women (mean age 82 years), 182 with subsequent hip fracture. FE models were generated from baseline DXA scans of the hip to determine femoral bone strength and load‐to‐strength ratio (LSR). The baseline LSR was significantly higher in fracture cases (median 1.1) compared with controls (0.7, p < 0.0001). Femoral strength and BMD were also significantly lower in cases (median 1820 N, 0.557 g/cm²) compared with controls (2614 N, 0.618 g/cm²) both p < 0.0001. Fracture risk increased per standard deviation decrease in femoral strength (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.8–2.8); femoral neck (FN) BMD (OR = 2.1, 95% CI 1.7–2.6); total hip BMD (OR = 1.8, 95% CI 1.5–2.1); and per SD increase in LSR (OR = 1.8, 95% CI 1.5–2.1). After adjusting for FN BMD, the odds ratio for femoral strength (OR = 1.7, 95% CI 1.2–2.4) and LSR (OR = 1.4, 95% CI 1.1–1.7) remained significantly greater than 1. The area under the curve (AUC) for LSR combined with FN BMD (AUC 0.69, 95% CI 0.64–0.73) was significantly greater than FN BMD alone (AUC 0.66, 95% CI 0.62–0.71, p = 0.004). Strength and LSR remained significant when adjusted for prevalent fragility fracture, VFA, and FRAX score. In conclusion, the DXA‐based FE model was able to discriminate incident hip fracture cases from controls in this longitudinal study independently from FN BMD, prior fracture, VFA, and FRAX score. Such an approach may provide a useful tool for better assessment of bone strength to identify patients at high risk of hip fracture who may benefit from treatment to reduce fracture risk. © 2013 American Society for Bone and Mineral Research.