Links between cardiovascular disease and osteoporosis in postmenopausal women : serum lipids or atherosclerosis per se ? Introduction and hypothesis Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa . Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood . We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage . Introduction Osteoporotic fractures and acute cardiovascular events remain the predominant contributors to morbidity and mortality among the elderly . Postmenopausal women with osteoporosis are at increased risk for acute cardiovascular events independent of their age and cardiovascular risk profile , and the increase in risk is proportional to the severity of osteoporosis at the time of the diagnosis -LSB- 1 -RSB- . Bone mineral density -LRB- BMD -RRB- at the hip is inversely correlated with the severity of aorta calcification -LRB- AC -RRB- and hence low hip BMD can be a surrogate marker of the atherosclerotic burden in elderly women -LSB- 2 -RSB- . Large cohort studies demonstrate that the rate of bone loss in metacarpals , proximal femur , and calcaneus is proportional to the progression of AC -LSB- 3 -- 5 -RSB- . Finally , advanced AC is associated with increased risk of osteoporotic fractures -LSB- 5 , 6 -RSB- . Collectively , numerous epidemiological observations document an overlap between the pathogenesis of the two diseases -LSB- 7 , 8 -RSB- . An attractive concept is that cardiovascular disease and osteoporosis are linked by a common denominator acting in parallel on both vascular and bone cells -LSB- 9 , 10 -RSB- . Plausible candidates of such linking factors are serum lipids , which in addition to their established role in atherogenesis , were also shown to act on osteoblasts -LSB- 11 -- 13 -RSB- and osteoclasts -LSB- 14 -RSB- under experimental conditions . Although some smaller cross-sectional studies found associations between lipid profile and BMD in humans -LSB- 15 -- 17 -RSB- , neither large population-based studies -LRB- e.g. , NHANES III -RRB- nor prospective studies support these initial observations -LSB- 18 , 19 -RSB- . A possible explanation the discrepancies could be that the true driver of the association is obstructive vascular disease , meaning that the association of lipids to bone is not detectable before the severity of intraluminal lesions reaches a critical grade when blood supply to the anatomical region is considerably hampered . Until now there have been no epidemiological studies that investigated associations of lipids and lipoprotein components with bone independent of a direct surrogate of the atherosclerotic burden . The aim of the present study was to test this hypothesis and investigate associations of a wide array of serum lipids and lipoproteins as well as of a genetic determinant of lipid profile with different surrogate measures of osteoporosis -LRB- BMD , fractures -RRB- and cardiovascular disease -LRB- AC , acute events -RRB- in 1176 Danish postmenopausal women providing full-set of data for such analyses . Subjects and methods Study population The study population consisted of 1176 generally healthy postmenopausal women participating in the PERF study . Details on recruiting have been described elsewhere -LSB- 20 -RSB- . This subpopulation was selected based on those whose BMD and body composition were measured by the same DXA scanner . The population characteristics were not statistically significant from the total PERF population indicating that the results reported herein are generally applicable to elderly Caucasian women 60 -- 85 years old . None of the women received any approved antiresorptive treatment or any other drugs with known effect on bone mass for more than 1 year . Forty-two patients reporting ongoing treatment with lipid-lowering drugs was excluded when analyzing associations of allelic variation in the ApoE gene with lipid profile . All women gave written their informed consent to participation and the study was carried out in compliance with the Helsinki Declaration II and the European Standards for Good Clinical Practice . The study protocol was approved by the local ethical committee . Demographic characteristics , risk factors , and clinical events Body weight and height were measured to the closest 0.1 kg and 0.1 cm , respectively , in women wearing light indoor clothing and no shoes . Body mass index -LRB- BMI -RRB- was calculated as body weight -LRB- in kg -RRB- divided by height squared -LRB- in m -RRB- . Information about age , years since menopause , smoking habits , regular alcohol and coffee consumption , weekly exercise , prevalent diabetes and cardiovascular diseases -LRB- stroke , coronary events , intermittent claudication , unstable angina -RRB- were collected during personal interview using a questionnaire -LSB- 20 -RSB- . Bone mineral density and fat mass measurement Bone mineral density -LRB- BMD -RRB- of the lumbar spine L1-4 and total hip was measured by dual energy X-ray absorptiometry -LRB- DEXA -RRB- using a QDR-2000 scanner -LRB- Hologic Inc. , Waltham , MA , USA -RRB- . Daily phantom scans were performed each morning for proper quality control . Body composition also was measured by the same whole-body scanner . The two components measured were total body fat mass -LRB- TFM -RRB- in kilograms and total lean mass in kilograms -LSB- 21 -RSB- . Total body fat mass was divided into two depots : central fat mass -LRB- CFM , subcutaneous and visceral fat mass of the trunk -RRB- and peripheral fat mass -LRB- PFM , subcutaneous fat mass of the legs and arms -RRB- . Body fat distribution was expressed by the CFM/PFM ratio , analogous to the well-known waist-to-hip ratio -LSB- 22 -RSB- . Fracture diagnosis Lateral X-rays of the thoracic and lumbar spine were performed using standard X-ray equipment . Vertebral deformities from T4 to L4 were assessed by digital measurements of vertebral deformations using the Image Pro Image Analyzer software -LRB- version 4.5 for windows , Media Cybernetics Inc. , Silver Spring , MD , USA -RRB- . The ratio of the anterior and posterior heights of each vertebral body was determined and a difference between the anterior and posterior edges exceeding 20 % was considered as a radiographic vertebral fracture . Information on prevalent non-vertebral fractures -LRB- wrist , hip , humeral fracture , rib , ankle , and foot -RRB- was collected during personal interview and later verified by X-rays or hospital discharge summaries . Grading of aorta calcification AC was assessed on lateral radiographs . Briefly , calcified deposits in the lumbar aorta adjacent to each lumbar vertebra -LRB- L1 -- L4 -RRB- were assessed separately for the anterior and posterior wall of the aorta using the midpoint of the inter-vertebral space as the boundaries . Each wall of each segment was graded for the presence of calcified deposits with a score from 0 to 3 -LRB- 0 : no deposits , 1 : less than one-third of the aortic wall , 2 : one-third to two-thirds of the aortic wall . 3 : more than two-thirds of the aortic wall covered with calcified deposits -RRB- . The sum of the scores of individual aortic segments both for the anterior and posterior walls , termed as anterior-posterior severity score and was used to describe the overall severity of AC in the lumbar aorta . Maximum score possibly given was 4 × 2 × 3 = 24 . The same investigator , who was blinded for all other results of the individual participants , carried out the evaluations . Intra-rater correlations between repeated measurements were in the range of r = 0.92 -- 98 -LRB- n = 50 -RRB- . Laboratory parameters Blood samples were collected in the morning after fasting overnight -LRB- > 12 h -RRB- . Serum total cholesterol , triglyceride , and high-density lipoprotein -LRB- HDL -RRB- cholesterol were determined by enzymatic assay using a Vitros-250 -LRB- Johnson & Johnson , Taastrup , Denmark -RRB- . LDL cholesterol was calculated by Friedewald formula -LRB- LDL − C = TC − HDL − C − 0.45 × TG -RRB- . Lipoprotein -LRB- a -RRB- , ApoA1 , and ApoB were measured by the Cobas Mira -LRB- Hoffman-La Roche , Mannheim , Germany -RRB- automatic blood analyzer . Genotyping DNA was isolated from peripheral blood samples . ApoE epsilon 2 , epsilon 3 and epsilon 4 alleles were determined by enzymatic amplification of genomic DNA followed by restriction enzyme treatment of the amplified products -LRB- Ossendorf and Prellwitz , Qiangen News 2000 , issue1 , 11 -- 13 -RRB- . Briefly , amplified products were treated with AflII and HaeII , respectively , and subjected to electrophoretic separation in agarose gels . The sequences of the amplification primers were 5 ' - ACTGACCCCGGTGGCGGAGGAGACGCGTGC-3 ' and 5 ' - TGTTCCACCAGGGGCCCCAGGCGCTCGCGG-3 ' . One of these primers was deliberately designed with a mismatch -LRB- underlined -RRB- to create a non-polymorphic AflIII site permitting assessment of the efficiency of the digestion process . Statistical analysis Results are presented as mean ± SD , unless otherwise indicated . Confounders of hip BMD and AC were identified by univariate correlation analysis . We classified ApoE genotypes into two categories marked by absence or presence of the ɛ4 allele . General linear models -LRB- GLM -RRB- tested the differences in selected dependent variables after adjustment for possible confounders . Similar approach was used to identify factors showing differences between women with or without fractures . Logistic regression models were established to assess the age-dependent and age-independent relative risk of wrist , hip , or vertebral fractures in women with advanced aorta calcification or cardiovascular disease . Statistical analyses were carried out using the SPSS data analysis software -LRB- version 12 , SPSS Inc. , Chicago , IL -RRB- . All statistical tests were two-tailed and differences were considered significant if the p-value was less than 0.05 . Results Demographic characteristics Demographic characteristics of the total population are shown in Table 1 . Less than one fifth of the population with an average age of 69.3 years had one or more manifestations of osteoporosis in form of a low BMD T-score equal or below − 2.5 and/or a fracture . In terms of cardiovascular status , the mean severity score of AC was 3.0 ± 3.8 and the number of women with history of an acute cardiovascular event was 50 -LRB- 4.3 % -RRB- . Table 1Demographic characteristics in the study populationCharacteristics and equivalent valuesNo . of women1176Age -LRB- years -RRB- 69.3 ± 6.4 Age at menopause -LRB- years -RRB- 48.7 ± 5.0 BMI -LRB- kg/m2 -RRB- 26.4 ± 4.4 Current smoking -LRB- % -RRB- 24.6 % Regular intake of alcohol -LRB- % -RRB- 55.2 % Serum total cholesterol -LRB- mmol/l -RRB- 6.3 ± 1.0 Serum triglyciders -LRB- mmol/l -RRB- 1.4 ± 0.7 Serum HDL -LRB- mmol/l -RRB- 1.7 ± 0.4 Serum LDL -LRB- mmol/l -RRB- 4.0 ± 0.9 Serum ApoA1 -LRB- mmol/l -RRB- 203.9 ± 37.1 Serum ApoB -LRB- mmol/l -RRB- 120.3 ± 24.5 Serum Lp -LRB- a -RRB- -LRB- mmol/l -RRB- 31.9 ± 34.6 ApoE ɛ4 allele carrier367 , 31.2 % Total hip BMD -LRB- g/cm2 -RRB- 0.80 ± 0.1 Lumbar spine BMD -LRB- g/cm2 -RRB- 0.92 ± 0.2 Hip BMD T-score ≤ − 2.5 -LRB- no . of women , % -RRB- 147 , 12.5 % Spine BMD T-score ≤ − 2.5 -LRB- no . of women , % -RRB- 179 , 15.2 % Vertebral fracture -LRB- no . of women , % -RRB- 204 , 17.6 % Hip fracture -LRB- no . of women , % -RRB- 16 , 1.4 % Aorta calcification3 .0 ± 3.8 Cardiovascular disease -LRB- no . of women , % -RRB- 50 , 4.3 % Data shown are mean ± SD . The ApoE genotype frequencies were 0.9 % -LRB- n = 11 -RRB- for ApoE ɛ2-2 , 12.7 % -LRB- n = 149 -RRB- for ApoE ɛ2-3 , 2.5 % -LRB- n = 29 -RRB- for ApoE ɛ2 -- 4 , 55.2 % -LRB- n = 649 -RRB- for ApoE ɛ3 -- 3 , 26.6 % -LRB- n = 313 -RRB- for ApoE ɛ3 -- 4 , and 2.1 % -LRB- n = 25 -RRB- for ApoE ɛ4 -- 4 , respectively . When classifying ApoE genotypes into absence of ApoE ɛ4 allele and presence of ApoE ɛ4 allele , 31.2 % -LRB- n = 367 -RRB- of women were ApoE ɛ4 allele carriers . These genotype proportions did not deviate significantly with those expected under conditions of Hardy-Weinberg equilibrium -LRB- X2 = 4.55 ; df = 3 ; p = 0.21 -RRB- , and they were similar to those previously reported for Danish populations -LSB- 22 , 23 -RSB- . Correlates of hip and spine BMD and AC In univariate analyses , summarized in Table 2 , AC showed direct correlation with age , CFM/PFM ratio , smoking , treated hypertension , and inverse association with physical exercise , regular alcohol consumption , BMI , and TFM % . On the other hand , BMI , TFM % and CFM/PFM ratio were significant direct , whereas age , years since menopause , and smoking were inverse correlates of both spine and hip BMD . Treated hypertension was significantly associated with spine BMD , whereas the severity score of AC was a significant inverse correlate of hip BMD -LRB- p < 0.05 -RRB- . Table 2Independent correlates of aorta calcification , hip BMD , and spine BMD -LRB- multiple regression models -RRB- Aorta CalcificationHip BMDSpine BMDAge0 .35 -LRB- p < 0.001 -RRB- − 0.23 -LRB- p < 0.001 -RRB- − 0.03 -LRB- p = 0.45 -RRB- YSM − 0.06 -LRB- p = 0.16 -RRB- − 0.06 -LRB- p = 0.10 -RRB- − 0.08 -LRB- p = 0.04 -RRB- BMI − 0.09 -LRB- p = 0.07 -RRB- 0.48 -LRB- p < 0.001 -RRB- 0.45 -LRB- p < 0.001 -RRB- TFM % − 0.04 -LRB- p = 0.36 -RRB- − 0.10 -LRB- p = 0.04 -RRB- − 0.21 -LRB- p < 0.001 -RRB- CFM/PFM ratio0 .08 -LRB- p = 0.02 -RRB- − 0.004 -LRB- p = 0.85 -RRB- 0.05 -LRB- p = 0.21 -RRB- Smoking0 .19 -LRB- p < 0.001 -RRB- − 0.05 -LRB- p = 0.10 -RRB- − 0.01 -LRB- p = 0.66 -RRB- Exercise − 0.03 -LRB- p = 0.25 -RRB- 0.04 -LRB- p = 0.17 -RRB- 0.04 -LRB- p = 0.21 -RRB- Treated hypertension0 .08 -LRB- p = 0.006 -RRB- 0.006 -LRB- p = 0.81 -RRB- 0.05 -LRB- p = 0.09 -RRB- Alcohol consumption − 0.08 -LRB- p = 0.007 -RRB- 0.06 -LRB- p = 0.04 -RRB- 0.07 -LRB- p = 0.02 -RRB- Apo e4 − 0.009 -LRB- p = 0.77 -RRB- 0.01 -LRB- p = 0.76 -RRB- − 0.03 -LRB- p = 0.22 -RRB- Triglyceride0 .02 -LRB- p = 0.63 -RRB- 0.03 -LRB- p = 0.43 -RRB- 0.04 -LRB- p = 0.32 -RRB- HDL-C0.05 -LRB- p = 0.48 -RRB- − 0.06 -LRB- p = 0.29 -RRB- 0.02 -LRB- p = 0.74 -RRB- LDL-CExcl.0 .02 -LRB- p = 0.73 -RRB- − 0.10 -LRB- p = 0.10 -RRB- Total cholesterol0 .05 -LRB- p = 0.43 -RRB- Excl.Excl.ApoA1 − 0.10 -LRB- p = 0.04 -RRB- 0.05 -LRB- p = 0.36 -RRB- 0.05 -LRB- p = 0.39 -RRB- ApoB0 .10 -LRB- p = 0.14 -RRB- − 0.03 -LRB- p = 0.60 -RRB- 0.10 -LRB- p = 0.85 -RRB- Aorta Calcification − 0.09 -LRB- p = 0.002 -RRB- 0.04 -LRB- p = 0.20 -RRB- R = 0.44 , SEE = 3.32 P < 0.001 R = 0.55 , SEE = 0.09 P < 0.001 R = 0.34 , SEE = 0.13 P < 0.001 Excl. : excluded from the model due to strong co-linearity . The independent role of the ApoE ɛ 4 allele Results of comparing lipids and lipoproteins between women with or without the ApoE ɛ4 allele are summarized in Table 3 . After adjustment for confounders , women with an ApoE ɛ4 allele had significantly higher serum total cholesterol , triglycerides , LDL-C , and ApoB levels than women without this allele . Furthermore , presence of the ApoE ɛ4 allele was associated with significantly lower HDL-C . In contrast , the differences in serum ApoA1 and Lp -LRB- a -RRB- did not reach statistical significance -LRB- Table 3 -RRB- . Finally , there were no significant differences in adjusted spine or hip BMD or the severity of AC -LRB- p > 0.05 -RRB- . Table 3Lipid and bone profile in women with or without an ApoE epsilon 4 allele Absence of ApoE epsilon 4 allele -LRB- n = 809 -RRB- Presence of ApoE epsilon 4 allele -LRB- n = 367 -RRB- P valueSerum total cholersterol * -LRB- mmol/l -RRB- 6.24 ± 0.036.51 ± 0.05 < 0.001 Serum triglycides * -LRB- mmol/l -RRB- 1.36 ± 0.021.48 ± 0.030.005 Serum HDL * -LRB- mmol/l -RRB- 1.72 ± 0.011.65 ± 0.020.006 Serum LDL * -LRB- mmol/l -RRB- 3.91 ± 0.034.19 ± 0.05 < 0.001 Serum ApoA1 * -LRB- mmol/l -RRB- 205.8 ± 1.3201.3 ± 2.00.06 Serum ApoB * -LRB- mmol/l -RRB- 117.3 ± 0.8127.2 ± 1.3 < 0.001 Serum Lp -LRB- a -RRB- * -LRB- mmol/l -RRB- 31.9 ± 1.329.2 ± 2.00.24 Total hip BMD -LRB- g/cm2 -RRB- * 0.803 ± 0.0040.804 ± 0.0050.89 Spine BMD -LRB- g/cm2 -RRB- * 0.924 ± 0.0050.915 ± 0.0080.32 Hip fracture1 .7 % 0.5 % 0.17 Vertebral fractures16 .4 % 19.3 % 0.24 Severity score of AC ** 2.81 ± 0.142.97 ± 0.210.13 Cardiovascular disease4 .0 % 4.9 % 0.44 Values are mean ± SEM . * Adjustment for age , years since menopause , BMI , TFM % , CFM/PFM ratio , current smoking , physical exercise , and regular alcohol consumption . ** Adjustment for the aforementioned confounders + treated hypertension . Associations of lipids with BMD and AC In univariate analysis -LRB- Table 2 -RRB- , total cholesterol and triglycerides were common correlates of spine BMD , hip BMD , and AC . HDL-C and ApoA1 were common correlates of AC and hip BMD -LRB- p < 0.05 -RRB- , whereas LDL-C , but not ApoB , was a common correlate of AC -LRB- p < 0.05 -RRB- . To obtain insights into the direct contribution of lipids to the variation of hip and spine BMD and the severity of AC , we established multiple regression models . The independent contributors to the variation in these surrogate markers are indicated in Table 2 . Lipids were not independent contributors to the variation in BMD when assessed in the presence of the severity of AC and other confounders . However , ApoA1 levels did seem to contribute to the variation in AC . Table 4Characteristics of women with or without at least one vertebral fracture Without vertebral fractureWith vertebral fracturep-valueAge68.9 ± 6.471.3 ± 6.4 < 0.001 YSM12 .7 ± 8.415.5 ± 8.6 < 0.001 BMI26 .4 ± 4.426.3 ± 4.4 NSTFM % 41.3 ± 7.640.7 ± 7.8 NSCFM/PFM ratio0 .88 ± 0.230.90 ± 0.24 NSRegular exercise73 .8 % 67.6 % 0.08 ApoE ɛ4 allele +30.5 % 34.8 % NSTotal cholesterol6 .32 ± 1.006.31 ± 1.04 NSTriglycerides1 .42 ± 0.691.31 ± 0.540.02HDL-C1.68 ± 0.431.71 ± 0.39NSLDL-C3.98 ± 0.934.01 ± 0.96 NSApoA1203 .8 ± 37.8204.6 ± 33.4 NSApoB120 .6 ± 24.5119.1 ± 24.5 NSLp -LRB- a -RRB- 31.7 ± 34.932.5 ± 33.5 NSSpine BMD0 .93 ± 0.150.87 ± 0.14 < 0.001 Hip BMD0 .82 ± 0.110.75 ± 0.11 < 0.001 Hip fracture1 .0 % 2.9 % 0.04 Wrist fracture11 .4 % 14.6 % 0.04 AC score2 .8 ± 3.73.5 ± 3.40.03 CVD3 .6 % 7.4 % 0.02 There were no significant differences in the frequency of smoking , regular alcohol , coffee , milk or seasonal vitamin D consumption , type 2 diabetes , treated hyperlipidemia or treated hypertension Comparison of women with or without fractures There were altogether 293 subjects who had an osteoporotic fracture after the menopause -LRB- i.e. , prevalent hip , vertebral , or wrist fracture -RRB- . Of the 204 women with at least one vertebral fracture , 33 also had a history of wrist fracture and 16 reported a history of hip fracture . Prevalence of non-vertebral fractures was significantly higher in women with compared with those without vertebral fracture -LRB- s -RRB- . Characteristics of women with or without vertebral fractures are summarized in Table 4 . Women with fractures were on average older and had a tendency for being physically less active . However , no significant differences in BMI , body adiposity , or body fat distribution were apparent . In addition , no significant differences in a wide array of lifestyle factors were apparent . When comparing the lipid profile of women with or without osteoporotic fractures after adjustment for potential confounders -LRB- i.e. , age , years since menopause , BMI , TFM % , CFM/PFM ratio , smoking , ApoE ɛ4 allele , physical exercise , alcohol consumption , and severity score of AC -RRB- , only triglycerides showed significant differences between the two groups -LRB- p < 0.05 -RRB- . Thus , triglycerides in women with and without fractures were 1.31 ± 0.04 mmol/l and 1.42 ± 0.03 mmol/l , respectively . When analyzing fracture types separately , the difference between women with or without hip or wrist fractures were not statistically significant . The relative risk of hip or vertebral fracture in women with severe AC or CVD To assess the implications of atherosclerotic vascular disease for osteoporotic fracture risk , we calculated the odds ratio of the different types of fractures in women with severe AC -LRB- ≥ 6 -RRB- and/or manifest CVD . As indicated in Table 5 , after adjustment for age , the risk of hip fractures but not wrist or vertebral fractures was increased in subjects with advanced vascular disease . Table 5Relative risk of different types of osteoporotic fractures in women with severe aorta calcification -LRB- score ≥ 6 -RRB- and/or manifest cardiovascular disease -LRB- n = 282 -RRB- Odds ratio -LRB- 95 % CI -RRB- p-valueHip fracture N = 16Crude4 .4 -LRB- 1.6 -- 12.9 -RRB- 0.001Age-adjusted3.0 -LRB- 1.1 -- 8.8 -RRB- 0.04 Vertebral fracture N = 204Crude1 .2 -LRB- 0.9 -- 1.7 -RRB- 0.27Age-adjusted1.0 -LRB- 0.7 -- 1.4 -RRB- 0.93 Wrist fracture N = 145Crude1 .4 -LRB- 1.0 -- 2.1 -RRB- 0.06Age-adjusted1.2 -LRB- 0.8 -- 1.7 -RRB- 0.46 Discussion In the present study , we investigated whether serum lipid and lipoproteins represent a biological linkage between osteoporosis and cardiovascular disease . The main findings were as follows : 1 -RRB- neither allelic polymorphism in the ApoE gene nor serum lipids per se were independent correlates of BMD at any skeletal site , 2 -RRB- ApoA1 levels were independent correlates of AC , which seem to play a role in the determination of hip BMD , 3 -RRB- decreased triglycerides were independently associated with vertebral fractures , but not with non-vertebral fractures -LRB- hip and wrist -RRB- , and 4 -RRB- advanced vascular disease was a significant contributor to risk of hip fractures , but not to vertebral or wrist fractures . These observations suggest that the role of lipids as linking factors between cardiovascular disease and osteoporosis is indirect via promotion of atherogenesis , which in turn can contribute to bone loss , especially at skeletal sites with end-arterial blood supply . Antiatherogenic measures can also be expected to contribute to decreasing the burden of hip fractures among the elderly . Univariate analysis pointed out several common correlates of BMD and atherosclerosis . Of these factors , aging , the duration of the menopause , BMI , and TFM % seemed to have reciprocal impact on BMD and AC . In multiple regression models , whereas BMI continued to correlate directly , TFM % became an inverse correlate of BMD . Accordingly , while weight-bearing may have a favourable impact on bone metabolism , adipose tissue accumulation exert an adverse influence . These findings corroborate the recent findings of Hsu YH et al. -LSB- 24 -RSB- . Although traditional views considered obesity a protective factor due to endogenous estrogen production , these more recent findings emphasize that other factors deriving from adipose tissue , e.g. , adipokines , inflammatory cytokines , and perhaps even lipids/lipoprotein metabolism are also to be taken into account . In addition , these findings also draw attention to the need of proper adjustment for overall adiposity and body fat distribution when addressing the direct implication of selected potential mediators . To address whether serum lipids represent a biological linkage between osteoporosis and vascular disease , one approach is to investigate whether polymorphism in a gene with known modulator effects on serum lipid profile is associated with variation in the severity of AC and BMD . Similar to previous observations -LSB- 25 , 26 -RSB- , we found that presence of the ɛ4 variant allele in the ApoE gene was independently associated with higher levels of total cholesterol , LDL-C and ApoB . In addition , we also observed subtle , yet statistically significant differences in serum triglycerides and HDL-C levels . Nevertheless , we were not able to document significant associations of the ɛ4 allele with either BMD or AC score . In male or mixed populations , the ɛ4 allele was reported as a risk factor for atherosclerosis -LSB- 27 , 28 -RSB- , suggesting that the association might be gender-specific for males . Total cholesterol and LDL-C are important predictors of cardiovascular risk in men , but less so in postmenopausal women in whom triglycerides and HDL-C carry greater importance -LSB- 29 , 30 -RSB- . Another explanation to the apparent discrepancies could be geographic variation in the relative importance of allelic variation in the ApoE gene . In support , a study in Finnish men reported higher importance of the ɛ3 allele for atherogenesis compared with the ɛ4 allele -LSB- 27 -RSB- . Similar discrepancies exist concerning the relative importance of this gene polymorphism for the determination of bone mass . Although there are reports suggesting that presence of the ɛ4 allele is a contributor to accelerated bone loss and/or increased risk of osteoporotic fractures -LSB- 31 , 32 -RSB- , not all studies confirm this finding , particularly those undertaken in women -LSB- 33 -- 35 -RSB- . Collectively , ApoE polymorphism with primary influence on total cholesterol , LDL-C , and apoB levels does not seem to provide a major biological linkage between the pathogenesis of osteoporosis and CVD . Experimental observations proposed LDL-C and HDL-C as common modulators of bone cells and vascular smooth muscle cells -LSB- 11 -- 14 -RSB- . On the clinical side , smaller cross-sectional studies found associations between lipid profile and BMD -LSB- 15 -- 17 -RSB- . However , none of these studies adjusted systematically for a direct DEXA measure of body fat distribution and/or smoking habits , which are important confounders of lipid profile . Our multiple regression analyses could not reveal significant independent associations of any of the considered lipid and lipoprotein components with hip or spine BMD . These findings are in line with the largest population-based observational study , the NHAEMS III survey including more than 13,000 subjects -LSB- 19 -RSB- . In further support , a recent longitudinal analysis of results from the Framingham study cohort reported insignificant direct influence of serum lipids for changes of BMD during a 25-year observational period -LSB- 18 -RSB- . Collectively , these observations do not seem to nurture the concept that serum lipids and lipoproteins exert clinically detectable direct effects on bone mineralization in elderly women . To further assess the potential implications of serum lipids and lipoproteins for osteoporosis , we also compared the profile of postmenopausal women with or without osteoporotic fractures . Interestingly , serum triglycerides were significantly lower in women with at least one vertebral fracture compared with those with no fractures , while no differences were seen between those with or without an osteoporotic non-vertebral fracture -LRB- i.e. , hip or wrist fracture -RRB- . This finding is similar to that reported by Yamaguchi et al. -LSB- 15 -RSB- . Since triglycerides were not associated with spine BMD , their direct contribution to fracture risk , if any , is via modulation of bone quality or bone strength . Given the cross-sectional design of this study , we can not exclude the possibility that a confounder or confounders of triglyceride levels , which was not considered herein is the actual modulator of bone fragility and hence fracture risk . Important finding of the multiple regression analysis was that the severity of AC was an independent correlate of hip BMD with no simultaneous independent contribution of lipids . This observation provides evidence that obstructive vascular disease rather than lipids/lipoproteins per se that drive bone loss from the hip . In a previous study , we showed that women with intermittent claudication have not only severe AC , but also very low BMD -LSB- 2 -RSB- . The direct contribution of atherosclerosis is also supported by the observation showing that asymmetric vascular disease is accompanied by asymmetric demineralization of this skeletal site -LSB- 36 -RSB- . Moreover , studies show that the rate of demineralization at the hip is significantly associated with the rate of atherogenesis -LSB- 5 -RSB- and even future risk of cardiovascular events -LSB- 37 -RSB- . On the other hand , we recently demonstrated in a large population-based cohort of postmenopausal women that accelerated atherogenesis is an independent predictor of hip fracture risk . Histological investigations of explants from elderly patients with femoral neck fractures indicate that both the larger -LRB- a. iliaca ext and a. femoris profunda -RRB- and the small vessels in the ligamentum teres supplying this skeletal site are frequently obstructed by atheromatous lesions -LSB- 38 , 39 -RSB- . These observations provide strong support for the important role of atherosclerosis for the pathogenesis of osteoporosis in the proximal femur . In summary , the results of the present observational study provide further evidence for the independent association of peripheral vascular disease with osteoporosis in the proximal femur . Since the association of lipids and lipoproteins to BMD and non-vertebral fractures is not independent of the severity of AC , it seems unlikely that these metabolites exert direct and clinically significant effects on bone turnover in postmenopausal women . Their contribution is via promotion of atherogenesis , in which regard ApoA1 levels seem to take a leading role . The remaining issue to be clarified is which genetic or environmental factors underlie the association of low triglycerides levels to vertebral fractures .

O O O O O B O O O O O B O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

aorta calcification
apoe polymorphism
cardiovascular events
lipids
osteoporosis


Effectiveness

of

bisphosphonates

on

nonvertebral

and

hip

fractures

in

the

first

year

of

therapy

The

risedronate

and

alendronate

-LRB-

REAL

-RRB-

cohort

study

Introduction

Randomized

clinical

trials

have

shown

that

risedronate

and

alendronate

reduce

fractures

among

women

with

osteoporosis

The

aim

of

this

observational

study

was

to

observe

in

clinical

practice

the

incidence

of

hip

and

nonvertebral

fractures

among

women

in

the

year

following

initiation

of

once-a-week

dosing

of

either

risedronate

or

alendronate

Introduction

Osteoporosis

a

common

skeletal

disease

in

older

populations

leads

to

more

than

a

million

fractures

annually

in

the

United

States

-LSB-

-RSB-

Nonvertebral

fractures

represent

of

osteoporotic

fractures

seen

in

clinical

practice

-LSB-

-RSB-

The

incidence

of

nonvertebral

fractures

especially

at

the

hip

increases

rapidly

with

age

-LSB-

-RSB-

In

order

to

prevent

these

fractures

US

clinical

guidelines

recommend

that

candidates

for

osteoporosis

therapy

be

identified

by

screening

the

bone

mineral

density

of

all

woman

ages

and

over

-LRB-

age

for

high

risk

populations

-RRB-

-LSB-

-RSB-

Oral

bisphosphonates

are

currently

the

most

common

therapy

for

osteoporosis

-LSB-

-RSB-

While

the

three

most

utilized

bisphosphonates

-LRB-

alendronate

risedronate

ibandronate

-RRB-

approved

by

the

Food

and

Drug

Administration

have

been

shown

to

reduce

vertebral

fractures

in

randomized

clinical

trials

it

is

unknown

if

these

three

are

equally

effective

in

reducing

nonvertebral

fractures

of

real-world

patients

in

clinical

practice

A

comparison

of

the

results

from

the

randomized

clinical

trials

of

each

bisphosphonate

though

limited

by

methodological

differences

between

trials

suggests

potential

differences

in

degree

of

fracture

reduction

across

bisphosphonates

In

the

primary

analyses

of

the

trials

that

followed

patients

for

at

least

years

risedronate

significantly

reduced

the

incidence

of

nonvertebral

fractures

by

up

to

-LSB-

-RSB-

alendronate

reduced

the

incidence

of

nonvertebral

fractures

by

up

to

-LSB-

-RSB-

ibandronate

did

not

reduce

nonvertebral

fractures

-LSB-

-RSB-

Post-hoc

analyses

of

these

trial

data

suggest

that

there

are

differences

in

the

onset

of

fracture

reduction

In

those

analyses

reduction

of

nonvertebral

fractures

began

at

months

for

mg

daily

dosing

of

risedronate

-LSB-

-RSB-

and

at

either

months

-LRB-

when

fractures

were

recorded

as

adverse

events

-RRB-

for

mg

daily

dosing

of

alendronate

-LSB-

-RSB-

or

months

for

mg

daily

dosing

of

alendronate

-LSB-

-RSB-

These

possible

differences

in

both

the

amount

and

the

onset

of

fracture

reduction

between

the

bisphosphonates

could

arise

from

their

differences

in

structure

potency

and

binding

properties

-LSB-

-RSB-

The

only

direct

comparison

of

bisphosphonates

in

a

randomized

clinical

trial

is

based

on

surrogate

endpoints

-LRB-

e.g.

changes

in

bone

mineral

density

and

markers

of

bone

turnover

-RRB-

-LSB-

-RSB-

However

the

association

between

changes

in

these

surrogates

and

subsequent

fracture

reduction

is

not

consistent

across

studies

-LSB-

-RSB-

Unlike

randomized

clinical

trials

based

on

surrogate

endpoints

observational

studies

of

large

populations

provide

the

opportunity

to

use

major

disease

endpoints

-LRB-

e.g.

hip

fracture

-RRB-

as

the

outcome

of

interest

The

limitation

of

observational

studies

can

be

misleading

results

from

bias

arising

from

non-randomized

treatment

groups

This

bias

can

be

accounted

for

in

part

by

statistically

adjusting

for

known

risk

differences

between

groups

Furthermore

when

different

therapies

are

available

to

be

prescribed

for

the

same

indication

there

is

at

least

some

expectation

of

similarity

in

prognostic

factors

between

treatment

groups

occurring

naturally

-LSB-

-RSB-

For

example

observational

studies

have

compared

both

the

many

antihypertensive

drug

therapies

and

many

statins

for

reducing

the

disease

endpoint

of

myocardial

infarctions

-LSB-

-RSB-

Since

the

once-a-week

dosing

regimens

of

both

risedronate

and

alendronate

have

been

available

in

the

US

since

there

is

now

an

opportunity

to

observe

their

effect

on

reducing

fractures

in

a

large

population

of

patients

seen

in

clinical

practice

Hence

we

conducted

an

observational

study

across

multiple

US

health

plans

to

observe

the

incidence

of

hip

and

nonvertebral

fractures

among

women

ages

and

over

following

initiation

of

therapy

with

once-a-week

dosing

of

either

risedronate

or

alendronate

Methods

The

RisedronatE

and

ALendronate

-LRB-

REAL

-RRB-

cohort

study

was

a

retrospective

observation

of

bisphosphonate

patients

within

healthcare

utilization

records

in

the

United

States

The

analysis

plan

was

based

upon

an

earlier

report

-LSB-

-RSB-

All

authors

had

access

to

the

data

For

assurance

of

reproducibility

-LSB-

-RSB-

the

analyses

were

independently

replicated

by

the

respective

organizations

of

the

authors

The

reporting

of

this

study

is

consistent

with

the

STROBE

guidelines

-LSB-

-RSB-

Data

source

The

data

source

was

commercially

available

datasets

of

healthcare

utilization

from

the

health

plan

within

Ingenix

Lab/Rx

-LRB-

Eden

Prairie

MN

data

through

June

-RRB-

and

the

health

plans

of

employers

within

MedStat

Marketscan

-LRB-

Ann

Arbor

MI

data

through

September

-RRB-

These

datasets

contain

a

longitudinal

history

of

patient-specific

data

including

demographic

information

-LRB-

sex

age

dates

of

dataset

inclusion

-RRB-

clinical

encounters

-LRB-

inpatient

and

outpatient

services

by

associated

procedures

and

diagnoses

specified

by

the

International

Classification

of

Diseases

Ninth

Revision

Clinical

Modification

-LRB-

-RRB-

-RRB-

and

outpatient

pharmaceutical

dispensations

-LRB-

retail

and

mail

order

specified

by

the

national

drug

code

-LRB-

NDC

-RRB-

-RRB-

To

maximize

sample

size

the

two

datasets

were

combined

for

all

analyses

At

the

time

of

data

extraction

for

the

current

study

the

combined

datasets

contained

million

persons

across

states

in

the

US

Study

population

Within

the

data

source

candidates

for

study

inclusion

were

all

women

aged

and

older

with

any

use

of

once-a-week

dosing

of

risedronate

-LRB-

mg

Actonel

P&G

Pharmaceuticals

-RRB-

or

once-a-week

dosing

of

alendronate

-LRB-

or

mg

Fosamax

MSD

-RRB-

after

July

a

date

corresponding

with

contemporaneous

commercial

availability

of

once-a-week

versions

of

both

therapies

-LRB-

Fig.

-RRB-

Patient

exclusion

criteria

and

rationale

were

-RRB-

less

than

months

-LRB-

days

-RRB-

of

health

plan

enrollment

before

their

first

bisphosphonate

use

after

July

a

history

period

to

measure

baseline

fracture

risk

-RRB-

less

than

months

-LRB-

days

-RRB-

of

health

plan

enrollment

after

their

first

bisphosphonate

use

a

minimum

observation

period

with

expectation

of

any

fracture

reduction

-LRB-

based

on

post-hoc

analyses

of

clinical

trials

-LSB-

-RSB-

-RRB-

-RRB-

any

bisphosphonate

use

-LRB-

daily

weekly

or

Paget

's

doses

-RRB-

during

their

month

history

period

to

include

only

patients

who

are

new

users

of

bisphosphonates

-RRB-

diagnosis

of

malignant

neoplasm

or

Paget

's

disease

during

either

the

month

history

period

or

first

months

of

observation

to

exclude

patients

with

fracture

risk

not

related

to

osteoporosis

and

-RRB-

discontinued

therapy

within

the

first

months

a

minimum

period

of

therapy

adherence

Fig.

of

the

study

population

Length

of

observation

Observation

for

a

subject

was

censored

at

one

of

following

end

points

whichever

occurred

first

date

of

fracture

months

after

date

of

first

bisphosphonate

prescription

end

date

of

health

plan

enrollment

date

of

switch

between

bisphosphonate

therapies

or

end

date

of

therapy

adherence

Adherence

was

measured

as

a

function

of

the

gaps

between

refills

which

provides

the

best

available

measure

within

datasets

of

medical

claims

-LSB-

-RSB-

Once

the

gap

between

the

completion

of

a

supply

and

the

start

of

a

new

prescription

exceeded

days

the

end

date

of

therapy

adherence

was

the

prescription

date

before

gap

plus

days

For

a

supply

a

gap

of

days

was

allowed

between

completion

and

a

new

prescription

the

end

date

of

therapy

adherence

was

the

prescription

date

before

gap

plus

days

For

the

last

prescription

the

end

date

of

therapy

adherence

was

the

date

of

last

prescription

plus

days

for

a

supply

and

date

of

last

prescription

plus

days

for

a

supply

Fracture

outcomes

From

the

data

source

two

outcomes

were

identified

subjects

with

nonvertebral

fractures

collectively

-LRB-

hip

wrist

humerus

clavicle

pelvis

leg

sites

previously

specified

-LSB-

-RSB-

-RRB-

and

subjects

with

a

hip

fracture

Vertebral

fractures

were

not

included

because

the

majority

of

them

do

not

come

to

clinical

attention

and

thus

not

systematically

captured

in

the

data

source

In

an

attempt

to

identify

incident

fractures

more

likely

related

to

osteoporosis

we

used

a

series

of

exclusion

criteria

-LRB-

Table

-RRB-

A

total

of

hip

and

nonvertebral

fracture

patients

were

available

for

analyses

Table

of

fractures

outcomes

in

the

study

population

-LRB-

n

-RRB-

Hip

fractureaNonvertebral

fracturebSubjects

with

a

medical

claim

for

fracture

during

the

observation

period

after

initial

bisphosphonate

Exclusion

of

medical

claim

if

a

fracture

at

the

same

site

both

before

and

after

start

of

bisphosphonate

therapy

in

order

to

increase

the

likelihood

of

including

only

new

fractures

of

medical

claim

if

a

fracture

at

an

unspecified

sitec

before

the

start

of

bisphosphonate

therapy

in

order

to

increase

the

likelihood

of

including

only

new

fractures

of

medical

claim

if

an

open

fractured

in

order

to

decrease

the

likelihood

of

including

traumatic

fractures

of

medical

claim

if

documented

cause

-LRB-

E-codes

-RRB-

of

injury

is

other

than

an

accidental

falle

in

order

to

decrease

the

likelihood

of

including

traumatic

fractures

with

a

fracture

codes

-LRB-

-RRB-

bIn

addition

to

inpatient

hip

fractures

inpatient

and

outpatient

codes

for

fracture

of

the

wrist

-LRB-

-RRB-

humerus

-LRB-

-RRB-

clavicle

-LRB-

-RRB-

pelvis

-LRB-

-RRB-

and

leg

-LRB-

-RRB-

code

-LRB-

or

-RRB-

code

that

is

not

x

or

where

the

digit

is

not

code

with

E

classification

-LRB-

-RRB-

for

accidental

falls

Statistical

analyses

To

assess

the

comparability

of

baseline

characteristics

-LRB-

see

Table

for

specific

definitions

of

demographic

characteristics

and

health

history

-RRB-

between

the

risedronate

and

alendronate

cohorts

the

chi-square

test

was

used

for

dichotomous

variables

and

the

Wilcoxon

rank

sum

test

was

used

for

continuous

variables

Table

of

baseline

characteristics

between

cohorts

in

study

CohortsCharacteristicRisedronateAlendronatep-valueNumber

of

women

Duration

of

observation

period

Days

-LRB-

mean

-RRB-

Age

at

study

entryYears

months

-LRB-

mean

-RRB-

Ages

-LRB-

-RRB-

Ages

-LRB-

-RRB-

Ages

and

over

-LRB-

-RRB-

Medications

month

historya

Concomitant

medications

-LRB-

mean

-RRB-

Gastrointestinal

medication

use

-LRB-

-RRB-

Estrogen

use

-LRB-

-RRB-

Other

non-estrogen

anti-osteoporotic

use

-LRB-

-RRB-

Glucocorticosteroid

use

-LRB-

-RRB-

Medical

encounters

month

historya

Office

visits

-LRB-

mean

-RRB-

Hospitalization

-LRB-

-RRB-

Osteoporosis

diagnosis

-LRB-

-RRB-

Osteopenia

diagnosis

-LRB-

-RRB-

Bone

densitometry

procedure

-LRB-

-RRB-

Gastrointestinal

diagnosis

-LRB-

-RRB-

Rheumatoid

arthritis

diagnosis

-LRB-

-RRB-

aSix

months

before

and

including

date

of

starting

first

bisphosphonate

prescriptionbBased

on

number

of

therapeutic

classes

with

a

prescription

-LSB-

-RSB-

cBased

on

NDC

codes

for

at

least

one

prescription

for

either

antagonists

-LRB-

ranitidine

cimetidine

famotidine

nizatidine

-RRB-

Proton

pump

inhibitors

-LRB-

omeprazole

esomeprazole

lansoprazole

pantoprazole

-RRB-

Cytoprotectives

-LRB-

misoprostol

sucralfate

-RRB-

-LSB-

-RSB-

dBased

on

NDC

codes

for

at

least

one

prescription

of

estradiol

conjugated

estrogen

esterified

estrogen

or

estropipateeBased

on

NDC

codes

for

at

least

one

prescription

of

calcitonin

or

raloxifenef

Based

on

NDC

codes

for

at

least

one

prescription

for

triamcinolone

prednisone

prednisolone

methylprednisolone

dexamethasone

budesonide

betamethasone

cortisone

or

and

no

record

of

xiCPT

jMultiple

codes

-LSB-

-RSB-

For

the

primary

analysis

the

main

outcome

measures

were

the

and

month

incidence

of

nonvertebral

fractures

and

hip

fractures

Cox

proportional

hazard

modeling

-LRB-

PROC

PHREG

SAS

Institute

Cary

NC

-RRB-

was

used

to

compare

the

incidence

of

fractures

between

risedronate

and

alendronate

cohorts

adjusting

for

potential

differences

in

measurable

risk

factors

for

fractures

A

parsimonious

model

for

each

outcome

was

developed

to

enhance

precision

of

the

parameter

estimates

and

interpretation

of

results

The

selection

of

variables

to

be

included

in

the

model

was

based

on

forward

selection

These

models

were

checked

against

models

based

on

backward

selection

The

appropriateness

of

the

proportional

hazard

assumption

was

assessed

by

graphical

and

numerical

methods

-LRB-

ASSESS

statement

SAS

Institute

-RRB-

In

order

to

evaluate

if

the

results

of

the

primary

analysis

were

dependent

on

methodology

sensitivity

analysis

were

used

to

compare

the

incidence

of

fractures

between

risedronate

and

alendronate

cohorts

These

methods

included

-LRB-

-RRB-

an

intent-to-treat

analysis

that

observed

all

subjects

for

months

regardless

of

therapy

adherence

-LRB-

-RRB-

a

proportional

hazard

model

using

the

propensity

score

to

adjust

for

differences

in

baseline

fracture

risk

between

cohorts

-LRB-

-RRB-

use

of

different

inclusion

criteria

for

the

study

population

-LRB-

-RRB-

use

of

different

inclusion

criteria

for

the

study

outcomes

-LRB-

see

Fig.

for

specifics

-RRB-

Results

The

risedronate

cohort

included

subjects

on

once-a-week

dosing

of

mg

followed

for

a

mean

of

days

on

therapy

of

this

cohort

was

censored

before

months

because

of

the

end

date

of

available

data

and

was

censored

for

an

end

in

therapy

adherence

The

alendronate

cohort

included

subjects

on

once-a-week

dosing

of

mg

-LRB-

-RRB-

or

mg

-LRB-

-RRB-

followed

for

a

mean

of

days

on

therapy

of

this

cohort

was

censored

before

months

because

of

the

end

date

of

available

data

and

was

censored

for

an

end

in

therapy

adherence

Upon

start

of

bisphosphonate

therapy

the

two

cohorts

were

different

in

several

baseline

characteristics

-LRB-

Table

-RRB-

Statistically

the

risedronate

cohort

was

older

had

more

concomitant

medications

had

more

use

of

glucocorticoids

and

had

more

patients

with

rheumatoid

arthritis

than

the

alendronate

cohort

characteristics

that

may

increase

fracture

risk

Conversely

the

risedronate

cohort

also

had

greater

past

use

of

calcitonin

or

raloxifene

a

characteristic

that

may

decrease

fracture

risk

Within

the

months

prior

to

the

initiation

of

bisphosphonate

therapy

similar

percentages

of

the

two

cohorts

had

a

diagnosis

for

a

nonvertebral

fracture

and

a

clinical

vertebral

fracture

while

a

statistically

larger

percentage

of

the

risedronate

cohort

had

a

diagnosis

for

a

hip

fracture

than

the

alendronate

cohort

-LRB-

Fig.

-RRB-

Fig.

of

patients

with

a

clinical

diagnosis

of

fracture

before

initiation

of

bisphosphonate

therapy

codes

codes

codes

-LRB-

-RRB-

of

study

population

with

available

month

history

Statistical

difference

-LRB-

p

-RRB-

between

cohorts

During

the

months

of

observation

after

the

start

of

bisphosphonate

therapy

subjects

had

nonvertebral

fractures

The

site

of

nonvertebral

fracture

was

wrist

-LRB-

-RRB-

hip

-LRB-

-RRB-

leg

-LRB-

-RRB-

pelvis

-LRB-

-RRB-

humerus

-LRB-

-RRB-

and

clavicle

-LRB-

-RRB-

For

the

women

hospitalized

with

a

hip

fracture

the

skeletal

sites

were

intertrochanteric

-LRB-

-RRB-

transcervical

-LRB-

-RRB-

unspecified

-LRB-

-RRB-

and

trochanteric

or

subtrochanteric

-LRB-

-RRB-

For

the

primary

analysis

of

nonvertebral

fractures

the

fracture

incidence

was

similar

between

the

risedronate

and

alendronate

cohorts

over

the

first

months

of

therapy

-LRB-

Fig.

-RRB-

After

months

of

therapy

the

risedronate

cohort

had

a

lower

-LRB-

CI

p-value

-RRB-

incidence

of

nonvertebral

fracture

than

the

alendronate

cohort

After

months

of

therapy

the

risedronate

cohort

had

an

lower

-LRB-

CI

p-value

-RRB-

incidence

of

nonvertebral

fracture

than

the

alendronate

cohort

-LRB-

Table

-RRB-

Fig.

incidence

of

nonvertebral

fractures

in

patients

treated

with

alendronate

or

risedronate

for

up

to

yearTable

incidence

of

fractures

during

therapyFracture

typeCohort

sizeNumber

of

women

with

a

fracturePercent

of

women

with

a

fractureaCrude

rate

ratiobAdjusted

rate

CIp-valueTime

on

therapy

Cohort

Months

Months

Months

Months

CI

confidence

interval

of

adjusted

rate

ratioaProportion

is

based

on

Kaplan-Meier

estimate

of

the

survival

function.bBased

on

Cox

regression

model.cBased

on

Cox

regression

model

Variables

selected

by

forward

stepwise

selection

where

criteria

for

selection

p

Model

for

nonvertebral

fractures

included

age

estrogen

use

number

of

medications

rheumatoid

arthritis

diagnosis

and

history

of

nonvertebral

fractures

Model

for

hip

fractures

included

age

estrogen

use

number

of

medications

and

history

of

hospitalization

For

the

primary

analysis

of

hip

fractures

the

fracture

incidence

was

similar

between

the

risedronate

and

alendronate

cohorts

over

the

first

months

of

therapy

-LRB-

Fig.

-RRB-

After

months

of

therapy

the

risedronate

cohort

had

a

lower

-LRB-

CI

p-value

-RRB-

incidence

of

hip

fracture

than

the

alendronate

cohort

After

months

of

therapy

the

risedronate

cohort

had

a

lower

-LRB-

CI

p-value

-RRB-

incidence

of

hip

fracture

than

the

alendronate

cohort

-LRB-

Table

-RRB-

Fig.

incidence

of

hip

fractures

in

patients

treated

with

alendronate

or

risedronate

for

up

to

year

These

differences

between

the

risedronate

and

alendronate

cohorts

in

the

incidence

of

fractures

were

consistent

across

other

methods

of

analysis

-LRB-

Fig.

-RRB-

Depending

on

the

method

the

risedronate

cohort

had

an

estimated

to

lower

incidence

of

nonvertebral

fractures

and

an

estimated

to

lower

incidence

of

hip

fractures

than

the

alendronate

cohort

through

months

of

therapy

All

of

these

other

estimates

were

within

the

confidence

intervals

of

the

primary

analyses

Fig.

analysis

Rate

ratio

for

fracture

in

the

first

year

of

therapy

between

patients

on

risedronate

and

patients

on

alendronate

results

of

the

primary

analysis

and

other

methods

of

analyses

Discussion

In

this

observational

study

across

multiple

US

health

plans

we

observed

that

patients

on

once-a-week

dosing

of

risedronate

had

a

lower

incidence

of

hip

and

nonvertebral

fractures

than

patients

on

once-a-week

dosing

of

alendronate

Differences

in

fracture

incidence

between

these

two

cohorts

of

patients

were

observed

at

and

months

after

initiating

therapy

As

with

all

observational

studies

systematic

errors

-LRB-

e.g.

selection

bias

measurement

misclassification

-RRB-

may

be

the

basis

for

the

observed

results

-LSB-

-RSB-

In

this

study

systematic

errors

may

arise

from

differences

in

fracture

risk

between

the

cohorts

of

patients

at

initiation

of

therapy

Between

the

two

cohorts

there

were

statistical

differences

in

measurable

fracture

risk

characteristics

-LRB-

Table

-RRB-

there

are

likely

to

be

differences

in

known

fracture

risk

characteristics

not

available

within

medical

claims

data

-LRB-

e.g.

bone

mineral

density

family

history

smoking

history

-RRB-

and

there

are

likely

to

be

differences

in

unknown

fracture

risk

characteristics

-LRB-

i.e.

those

that

are

controlled

through

randomized

trials

-RRB-

The

differences

in

measurable

fracture

risk

characteristics

for

which

a

greater

percentage

of

the

risedronate

cohort

has

risk

factors

for

fracture

than

the

alendronate

cohort

suggesting

bias

towards

higher

fracture

rates

in

the

risedronate

cohort

are

inconsistent

with

observed

results

The

near

unity

in

fracture

incidence

between

the

two

cohorts

during

the

first

months

of

therapy

-LRB-

Figs.

and

-RRB-

a

period

for

which

there

is

also

unity

in

fracture

incidence

between

bisphosphonate

therapy

and

placebo

in

clinical

trials

-LSB-

-RSB-

suggest

that

both

cohorts

had

similar

risk

for

fracture

at

initiation

of

therapy

However

differences

in

fracture

risk

at

initiation

of

therapy

between

the

two

cohorts

can

not

be

excluded

Within

healthcare

utilization

data

which

are

collected

for

purposes

other

than

research

misclassification

of

fracture

events

and

of

therapy

use

are

inevitable

As

a

check

on

the

data

the

rate

of

fracture

events

and

therapy

use

of

these

health

utilization

data

are

in

agreement

with

other

data

sources

In

the

current

study

the

annual

fracture

rates

following

initiation

of

therapy

-LRB-

for

nonvertebral

fractures

and

for

hip

fractures

-RRB-

are

consistent

with

the

annual

rates

in

the

treated

population

of

clinical

trials

-LRB-

between

and

for

nonvertebral

fractures

and

between

and

for

hip

fractures

-LSB-

-RSB-

-RRB-

In

this

study

risedronate

patients

constituted

-LSB-

-LRB-

-RRB-

-RSB-

of

the

bisphosphonate

users

in

the

utilization

data

compared

to

-LSB-

million

-LRB-

million

million

-RRB-

-RSB-

of

all

bisphosphonate

prescriptions

in

the

US

during

the

same

period

-LSB-

-RSB-

A

good

method

for

evaluating

misclassification

within

healthcare

utilization

data

is

through

a

medical

chart

review

In

a

prior

study

the

proportion

of

fracture

claims

confirmed

by

chart

review

to

be

a

fracture

was

highest

for

the

hip

relative

to

other

fracture

sites

-LSB-

-RSB-

Since

the

effect

of

misclassification

at

these

other

fracture

sites

is

likely

to

be

no

different

between

cohorts

-LRB-

i.e.

misclassified

exposure

does

not

depend

on

cohort

status

-RRB-

the

study

results

for

nonvertebral

outcomes

are

likely

more

attenuated

by

misclassification

than

results

for

the

hip

-LSB-

-RSB-

The

strength

of

observational

studies

can

be

the

generalizability

of

results

In

contrast

the

generalizability

of

results

from

randomized

trials

to

a

real

world

setting

can

be

limited

by

differences

between

the

two

in

relation

to

expertise

of

health

care

provider

quality

of

medical

care

course

of

therapy

and

types

of

patients

-LSB-

-RSB-

For

example

it

has

been

observed

that

the

majority

of

patients

considered

candidates

for

osteoporosis

therapy

by

their

physician

would

not

meet

the

eligibility

criteria

for

inclusion

in

the

randomized

trials

-LSB-

-RSB-

Since

the

population

within

the

current

observational

study

is

drawn

from

multiple

health

plans

in

many

US

states

and

consists

of

subjects

with

a

mixture

of

health

characteristics

-LRB-

e.g.

prior

gastrointestinal

comorbidities

-RRB-

the

results

are

likely

to

be

generalizable

Furthermore

the

length

of

observation

of

therapy

adherence

-LRB-

days

-RRB-

in

the

current

study

was

consistent

to

the

previously

reported

average

duration

of

adherence

to

bisphosphonate

therapy

-LRB-

days

-RRB-

-LSB-

-RSB-

In

conclusion

within

this

observational

study

of

clinical

practice

a

cohort

of

patients

receiving

risedronate

had

lower

rates

of

hip

and

nonvertebral

fractures

during

their

first

year

of

therapy

than

a

cohort

of

patients

receiving

alendronate

These

results

do

not

appear

to

be

explained

by

baseline

differences

in

fracture

risk

between

cohorts

In

addition

the

observed

rates

of

fracture

were

consistent

with

the

fracture

rates

in

clinical

trials

Thus

it

appears

patients

receiving

risedronate

are

better

protected

from

hip

and

nonvertebral

fractures

during

their

first

year

of

therapy

than

patients

receiving

alendronate

O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O

bisphosphonates
hip fractures
nonvertebral fractures
osteoporosis


Focal segmental glomerulosclerosis -- epidemiology aspects in children and adults The histologic features of idiopathic forms of focal segmental glomerulosclerosis -LRB- FSGS -RRB- were first described by Theodor Fahr in the Handbuch der speziellen pathologischen Anatomie und Histologie in 1925 -LSB- 1 -RSB- . Over the subsequent eight decades much has been written about the histologic features and clinical characteristics of patients with FSGS , but it is only in recent years that attention has been directed to the incidence and prevalence of the disorder in various populations . This article will provide an overview of the epidemiology of FSGS by reviewing published surveys of renal biopsies , experiences from clinical registries of children with renal insufficiency , and data from the U.S. Renal Data Systems -LRB- USRDS -RRB- . Diagnostic considerations Primary FSGS can present at any age , and it always causes proteinuria . It is most commonly diagnosed in patients with overt nephrotic-range proteinuria , but any proteinuria that is fixed and persistent over several months -LRB- i.e. , not orthostatic or transient proteinuria -RRB- may signal underlying FSGS -LSB- 2 , 3 -RSB- . Since the diagnosis of FSGS depends on obtaining renal histologic material , the observed incidence and demographics of FSGS in both children and adults depend on the population examined and on the indications used for renal biopsy . The typical findings on renal biopsy in idiopathic FSGS are described elsewhere in this series of articles . Incidence and prevalence of FSGS in children An estimation of the incidence and prevalence of FSGS in children is hampered by the fact that most children with nephrotic syndrome -LRB- NS -RRB- , unlike the majority of adults , are not routinely subjected to renal biopsy . Therefore , prevalence and incidence figures are extrapolated from clinical reports , registries , and renal biopsy materials . Clinical reports often make the presumptive diagnosis of minimal change nephrotic syndrome -LRB- MCNS -RRB- based on steroid responsiveness -LSB- 4 , 5 -RSB- . This usually leads to an under-diagnosis of FSGS because up to 15 -- 20 % of FSGS patients initially respond to steroids -LSB- 6 -RSB- . The largest pediatric registry is that of the North American Pediatric Renal Transplant Cooperative Study -LRB- NAPRTCS -RRB- , which collects data not only on transplant patients but also on dialysis and chronic kidney disease -LRB- CKD -RRB- patients -LSB- 6 -RSB- . Based on results from nearly 6000 children with CKD , in whom the estimated glomerular filtration rate -LRB- GFR -RRB- was less than 75 ml/min per 1.73 m2 , it has been shown that FSGS carries the highest likelihood of progressing to end-stage renal disease -LRB- ESRD -RRB- , exceeding the risk of hypoplasia , obstructive uropathy , and reflux nephropathy . According to NAPRTCS data , nearly 60 % of such children with a diagnosis of FSGS progress to dialysis or transplantation within 24 months of entry into the registry . However , because reporting is entirely voluntary and involves mainly pediatric centers , there is significant underreporting , and selection bias may exist . Clinical surveys from North America and the United Kingdom have reported the incidence of NS to be between two and four new cases per 100,000 children per year , with biopsy-confirmed FSGS comprising 15 -- 20 % of the total -LSB- 5 , 7 -- 10 -RSB- . However , as noted above , many children with NS do not undergo a diagnostic renal biopsy unless they are shown to be steroid-resistant . A study from Canada reported an incidence of FSGS of 0.37 to 0.94 new cases per 100,000 children per year -LSB- 5 -RSB- , and similar results were obtained in the U.S. Midwest -LSB- 9 -RSB- . In the NAPRTCS database , patients with FSGS account for 14.2 % of dialysis patients and for 11.5 % of transplant patients ; the differences may reflect a reluctance by some centers to transplant FSGS patients for fear of disease recurrence . Members of the Southwest Pediatric Nephrology Study Group -LRB- SPNSG -RRB- reported that FSGS was diagnosed in 75 of 1053 -LRB- 7.1 % -RRB- patients with NS who underwent a renal biopsy between 1972 and 1981 -LSB- 11 -RSB- . While there is a male preponderance among children with MCNS , most reports have described no clear gender difference in patients with FSGS -LSB- 4 , 11 , 12 -RSB- , although in the SPNSG series , all 18 children with FSGS below the age of 3 years were boys -LSB- 11 -RSB- . Ethnicity and age appear to play important roles in the prevalence of FSGS . The NAPRTCS and SPNSG reports include approximately equal numbers of Caucasian and African American children with FSGS despite the large difference in the racial distribution of the underlying populations -LSB- 6 , 11 -RSB- . According to the NAPRTCS report , FSGS is the most common cause of ESRD in African-American children in that cohort , accounting for 23 % of all pediatric patients with ESRD . In Caucasian children , FSGS is only the third most common primary disease and is responsible for approximately 10 % of all pediatric patients with ESRD -LSB- 5 -RSB- . In contrast , African-American children with NS appear to be more likely to have FSGS than MCNS -LSB- 4 , 10 , 13 -RSB- . Whether the frequency of FSGS in Hispanic children differs from that in Caucasians is unclear -LSB- 14 , 15 -RSB- . The prevalence of FSGS among all children with NS who undergo a renal biopsy increases with age . However , it is not clear if the true population-based incidence of FSGS is age-dependent . Two thirds of children with NS present before the age of 6 years , but only a minority of the younger children exhibit FSGS , whereas FSGS is the most common histology in the older group . The frequency of FSGS in NS patients presenting before 6 years of age is less than 10 % , but increases to 20 -- 50 % or more in patients presenting in adolescence -LSB- 4 , 9 -- 11 , 16 -RSB- . The combined effect of age and ethnicity is responsible for the reported high frequency of FSGS in kidney biopsies from adolescent African-American patients with NS -LSB- 4 , 10 , 13 -RSB- ; both age and ethnicity are probably independent risk factors for FSGS histology . An intriguing recent development has been the apparent increase in the incidence of FSGS in children -LSB- 4 , 5 , 10 , 17 -RSB- . Differences in the ages and ethnicity of the subjects do not fully explain these findings . Filler et al. , for instance , studied mostly Caucasian children in Canada and found that the calculated incidence of FSGS increased from 0.37 to 0.94 per 100,000 children per year from the first to the second half of a 17-year period between 1985 and 2002 -LSB- 5 -RSB- . The increase appears to be present mostly in older children -LSB- 4 -RSB- . Similar increases in incidence have not been seen in other types of NS in children -LSB- 4 , 5 -RSB- . The cause of the increased incidence is not known but is unlikely to be due to genetic factors . The role of environmental pollution has been proposed but remains hypothetical -LSB- 18 -RSB- . Morbid obesity-associated FSGS has increased in renal biopsy material -LSB- 19 -RSB- , but because it remains uncommon , the current adult and pediatric obesity epidemic probably does not explain the increase in FSGS . Incidence and prevalence of FSGS in adults Several publications suggest that the prevalence of idiopathic FSGS in adults may also be increasing -LSB- 20 , 21 -RSB- . Observations from two metropolitan centers suggest that FSGS was found in 2.5 -- 4 % of native renal biopsies in the 1970s , but in 12.2 -- 18.7 % in this decade , making FSGS the most common diagnosis based on native kidney biopsies . FSGS becomes less common with advancing age , but it is still a significant problem in the elderly . In a series of 1368 renal biopsies from patients over 60 years of age , FSGS was present in 5.4 % of those patients with nephrotic syndrome -LSB- 20 -RSB- . These trends in increased numbers of FSGS cases are observed in both African Americans and Caucasians and occurred despite stable or falling rates of other glomerular diseases , such as minimal change disease and membranous nephropathy -LSB- 21 -RSB- . Two large series in adults support the fact that primary FSGS is a risk factor for developing ESRD . In one report of outcomes from immunosuppressive therapy in 59 adult patients with FSGS , 30 % of patients developed some level of renal insufficiency within 5 years -LSB- 22 , 23 -RSB- . Wehrmann and colleagues reported results from 250 patients with idiopathic FSGS -LRB- average age : 32 years -RRB- in which they found an overall 10-year renal survival of 67 % -LSB- 23 -RSB- . The risk of developing ESRD in idiopathic FSGS can be predicted at the time of diagnosis . Heavy proteinuria , either at the time of biopsy but particularly following treatment , portends a poor long-term outcome . Other features that increase the risk for progressive renal disease include elevated serum creatinine at the time of diagnosis , hypertension , age at time of diagnosis , and male gender -LSB- 22 , 24 , 25 -RSB- . The most compelling predictor for progression of FSGS , however , appears to be the response of proteinuria after treatment is initiated . One series suggests that if a patient with primary FSGS fails to respond to initial therapy -LRB- most often steroid-based -RRB- , the likelihood of renal death is as great as if the patient received no treatment at all -LSB- 25 -RSB- . However , a full assessment of relative risk will require larger cohorts of patients with FSGS who received consistent interventions . The risk of FSGS-related ESRD in adults is also supported by data published by the USRDS -LSB- 26 -RSB- . Documented FSGS accounts for more than 7000 patients currently receiving ESRD therapy in the United States , and it is likely that primary FSGS accounts for at least some of the 25,000 patients with unspecified forms of glomerulonephritis , the 100,000 patients with ESRD attributed to hypertension , and the 20,000 patients with an unknown cause of ESRD -LSB- 26 -RSB- . The USRDS also demonstrates a dramatic increase in the incidence of ESRD due to FSGS , particularly over the last decade in the African-American population . In the Caucasian U.S. population , new-onset ESRD due to FSGS has slowly increased to a rate of approximately five cases/million population in 2003 . In contrast , the incidence has increased nearly five-fold in the African-American population since the early 1980s to 30 -- 40 cases per million population -LSB- 26 -RSB- . Familial FSGS Occasional cases of familial FSGS have long been recognized . In 1973 Habib suggested that 12 % of all pediatric cases of FSGS had an affected sibling -LSB- 2 -RSB- . Although most cases of FSGS are sporadic with unknown pathophysiology , it is now clear that mutations in structural podocyte-associated proteins account for a portion of familial cases and for at least some of the sporadic cases . A mutation in the NPHS2 gene , which encodes the protein podocin , has been linked to autosomal-recessive steroid-resistant nephrotic syndrome in children -LSB- 27 -RSB- . However , there are large differences between different ethnic populations . For example , approximately one third of Israeli-Arab children but none of Israeli-Jewish or Japanese children with sporadic FSGS were reported to have NPHS2 mutations -LSB- 27 , 28 -RSB- . The frequency of NPHS2 mutations in North American children is not known . Mutations in the a-actinin 4 gene -LRB- ACTN4 -RRB- have been associated with autosomal-dominant FSGS in adults , a disease characterized by a variable risk of progression to ESRD . Most recently , autosomal-dominant FSGS has been linked to the gene that encodes the transient receptor potential cation channel , subfamily C , member 6 -LRB- TRPC6 -RRB- -LSB- 29 -RSB- . Although more data are needed , it is likely that mutations in the known FSGS causative genes account for only a minority of cases of FSGS in children and adults . A more complete review of the genetic aspects of FSGS is provided elsewhere in this series of articles . Conclusion It is clear that there is still much to learn about the epidemiology of idiopathic FSGS . However , there are encouraging signs that the body of knowledge will be enhanced in coming years by the various registries and population-based studies currently underway . Questions -LRB- Answers appear following the reference list -RRB- Which of the following statements is correct ? Patients with idiopathic FSGS often present with microscopic hematuria without proteinuria.All patients with FSGS have nephrotic range proteinuria.Patients with FSGS have proteinuria of varying severity.None of the above.Which of the following carries the highest risk for a patient with FSGS to progress to ESRD ? Male gender.Persistent proteinuria after therapy.Hyperlipidemia.Caucasian race.Age.Which of the following is incorrect ? Accurate data concerning the outcome of patients with FSGS is lacking since the disease was first described only 30 years ago.The incidence of the disease appears to be decreasing in the last 20 years.Most cases of FSGS can now be linked to specific gene mutations that disturb podocyte function.All of the above.None of the above.Which of the following is correct ? FSGS is a more frequent cause of ESRD in Caucasian children than in African-American children.FSGS is more commonly associated with nephrotic syndrome in Hispanic children than in white children.Children with FSGS account for less than 10 % of African-American children who progress to ESRD.All of the above.None of the above .

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epidemiology
focal segmental glomerulosclerosis
nephrotic syndrome