a case  control study was performed using the dutch pharmo record linkage system ( rls ) database ( www.pharmo.nl ) .
the database contains pharmacy dispensing data ( including dispensed drug , type of prescriber , dispensing date , amount dispensed , and written dosage instructions ) of about 1 million dutch residents , linked to a nationwide hospital discharge register .
diagnoses are coded according to the international classification of diseases , 9th revision ( icd-9 ) .
patients are included irrespective of health insurance or socioeconomic status and represent about 7% of the general population .
the pharmo rls database has a high level of completeness , as shown in several independent validation studies .
cases were defined as patients who had sustained their first hip fracture during the 10-year study period ( 1 january 1991 to 31 december 2002 , at least 18  years of age ) . up
to four controls were selected for each case , matched by year of birth , gender , and geographic location .
control patients were registered in the database and had no record for a hip fracture hospitalization .
, we restricted the study population to subjects who were at least 50  years of age at the index date .
history of primary ka before index date was determined using icd-9 surgical procedure code 81.54 .
time since onset (  recency  ) of the ka was determined by calculating the time between the index date and the earliest hospital admission for the ka .
we created a proxy for unilateral / bilateral ka by stratifying ka patients into ( 1 ) subjects with one primary ka record before the index date and ( 2 ) those with multiple primary ka records before the index date . in a sensitivity analysis , we stratified patients who had undergone a ka to the region of the body in which oa was recorded .
we used icd-9 codes 715.6 ( oa of lower leg ) as well as 715.0715.5 and 715.7715.9 ( oa of other or unspecified regions ) to identify a history of oa .
in addition , time since onset of oa was calculated similarly to that of time since ka .
odds ratios ( ors ) for fracture risk were estimated using conditional logistic regression ( sas version 9.1.3 , phreg procedure ; sas institute , cary , nc ) .
the following risk factors were considered as potential confounders : use of benzodiazepines in the 3  months before the index date ; use of bronchodilators , inhaled corticosteroids , oral corticosteroids [ 12 , 13 ] , statins , antipsychotics , lithium , antidepressants , beta - blockers , opioids ( tramadol and stronger ) , antiepileptics , thiazide diuretics , renin  angiotensin 
aldosterone system inhibitors , acid suppressants , two or more dispensings of a nonsteroidal anti - inflammatory drug ( nsaid ) , disease - modifying antirheumatic drugs , organic nitrates , antidiabetic drugs , bisphosphonates , hormone - replacement therapy , calcium / vitamin d supplements , digoxin , and other antiarrhythmics within the 6  months before the index date . in addition , a diagnosis of anemia , mental disorders , impaired renal functioning , skin or subcutaneous disease , any serious injury within the year before the index date , or a history of malignant neoplasm , endocrine disorder , cardiovascular disease , obstructive airways disease , inflammatory bowel disease , musculoskeletal diseases ( excluding oa ) , and connective tissue diseases or rheumatoid arthritis ever before index date were considered as potential confounders .
parameters were included in the final regression model if they independently changed the beta coefficient for arthroplasty with > 5% in the logistic regression model . in a sensitivity analysis , we included use of bisphosphonates and hormone - replacement therapy within 6  months before index date in the final regression model , regardless of the change in beta coefficient for arthroplasty caused by these treatments . the longitudinal relationship between the risk of hip fracture and time since ka was visualized using a smoothing spline regression plot ( sas version 9.1.3 , gplot procedure ) .
a case  control study was performed using the dutch pharmo record linkage system ( rls ) database ( www.pharmo.nl ) .
the database contains pharmacy dispensing data ( including dispensed drug , type of prescriber , dispensing date , amount dispensed , and written dosage instructions ) of about 1 million dutch residents , linked to a nationwide hospital discharge register .
diagnoses are coded according to the international classification of diseases , 9th revision ( icd-9 ) .
patients are included irrespective of health insurance or socioeconomic status and represent about 7% of the general population .
the pharmo rls database has a high level of completeness , as shown in several independent validation studies .
cases were defined as patients who had sustained their first hip fracture during the 10-year study period ( 1 january 1991 to 31 december 2002 , at least 18  years of age ) . up
to four controls were selected for each case , matched by year of birth , gender , and geographic location .
control patients were registered in the database and had no record for a hip fracture hospitalization .
, we restricted the study population to subjects who were at least 50  years of age at the index date .
history of primary ka before index date was determined using icd-9 surgical procedure code 81.54 .
time since onset (  recency  ) of the ka was determined by calculating the time between the index date and the earliest hospital admission for the ka .
we created a proxy for unilateral / bilateral ka by stratifying ka patients into ( 1 ) subjects with one primary ka record before the index date and ( 2 ) those with multiple primary ka records before the index date . in a sensitivity analysis , we stratified patients who had undergone a ka to the region of the body in which oa was recorded .
we used icd-9 codes 715.6 ( oa of lower leg ) as well as 715.0715.5 and 715.7715.9 ( oa of other or unspecified regions ) to identify a history of oa .
in addition , time since onset of oa was calculated similarly to that of time since ka .
odds ratios ( ors ) for fracture risk were estimated using conditional logistic regression ( sas version 9.1.3 , phreg procedure ; sas institute , cary , nc ) .
the following risk factors were considered as potential confounders : use of benzodiazepines in the 3  months before the index date ; use of bronchodilators , inhaled corticosteroids , oral corticosteroids [ 12 , 13 ] , statins , antipsychotics , lithium , antidepressants , beta - blockers , opioids ( tramadol and stronger ) , antiepileptics , thiazide diuretics , renin  angiotensin  aldosterone system inhibitors , acid suppressants , two or more dispensings of a nonsteroidal anti - inflammatory drug ( nsaid ) , disease - modifying antirheumatic drugs , organic nitrates , antidiabetic drugs , bisphosphonates , hormone - replacement therapy , calcium / vitamin d supplements , digoxin , and other antiarrhythmics within the 6  months before the index date .
in addition , a diagnosis of anemia , mental disorders , impaired renal functioning , skin or subcutaneous disease , any serious injury within the year before the index date , or a history of malignant neoplasm , endocrine disorder , cardiovascular disease , obstructive airways disease , inflammatory bowel disease , musculoskeletal diseases ( excluding oa ) , and connective tissue diseases or rheumatoid arthritis ever before index date were considered as potential confounders .
parameters were included in the final regression model if they independently changed the beta coefficient for arthroplasty with > 5% in the logistic regression model . in a sensitivity analysis , we included use of bisphosphonates and hormone - replacement therapy within 6  months before index date in the final regression model , regardless of the change in beta coefficient for arthroplasty caused by these treatments .
the longitudinal relationship between the risk of hip fracture and time since ka was visualized using a smoothing spline regression plot ( sas version 9.1.3 , gplot procedure ) .
table  1 shows baseline characteristics of the fracture cases and controls . as expected ( due to matching ) , cases and controls had a similar age and gender distribution .
fracture cases had recently used more medication that has been associated with fracture , such as oral glucocorticoids and strong opioid analgesic . compared to controls ,
they had more often a history of comorbid conditions.table  1characteristics of hip fracture cases and controlscharacteristiccases ( % ) controls ( % ) ( n  =  6,763)(n  =  26,341)gender  female4,929 ( 72.9)19,138 ( 72.7)age ( years )  18701,641 ( 24.3)6,554 ( 24.9 )  71802,144 ( 31.7)8,496 ( 32.3 )  > 802,978 ( 44.0)11,291 ( 42.9)use 6  months prior to index date  oral glucocorticoids366 ( 5.4)918 ( 3.5 )  paracetamol882 ( 13.0)2,247 ( 8.5 )  > 1 nsaid929 ( 13.7)2,584 ( 9.8 )  opioids253 ( 3.7)455 ( 1.7 )  dmards115 ( 1.7)202 ( 0.8 )  antipsychotics412 ( 6.1)921 ( 3.5 )  calcium / vitamin d supplements362 ( 5.4)894 ( 3.4)hospitalization ever prior to index date  osteoarthritis220 ( 3.3)773 ( 2.9 )  rheumatoid arthritis245 ( 3.6)731 ( 2.8 )  musculoskeletal / connective tissue disease ( excluding osteoarthritis)469 ( 6.9)1,328 ( 5.0 )  endocrine disorders199 ( 2.9)381 ( 1.4 )  obstructive airway disease266 ( 3.9)643 ( 2.4)nsaid nonsteroidal anti - inflammatory drug , dmard disease - modifying antirheumatic drug characteristics of hip fracture cases and controls nsaid nonsteroidal anti - inflammatory drug , dmard disease - modifying antirheumatic drug table  2 shows the relationship between time since ka and the risk of hip fracture . in the adjusted analysis , we found a 54% increased risk of hip fracture among patients with ka ( adjusted [ adj . ] or  =  1.54 , 95% confidence interval [ ci ] 1.161.99 ) . in the sensitivity analysis ,
use of bisphosphonates and hormone - replacement therapy within 6  months before index date did not substantially change the increased risk ( adj . or  =  1.54 , 95% ci 1.192.00 ) .
similarly , the increased risk was not changed when looking at subjects aged 50  years only ( 93.2% of the study population ; adj . or  =  1.55 , 95% ci 1.192.01 ) .
there was a suggestion that the increased risk of hip fracture was greatest in the first few years after the first ka ( fig .  1 ) ,
no substantial differences were found with regard to the proxy for unilateral ( adj . or  =  1.40 , 95% ci 1.011.95 ) and bilateral ( adj . or  =  1.81 , 95% ci 1.202.74 ) ka ( p  =  0.34 ) .
furthermore , timing of increased hip fracture risk following the most recent ka was comparable between the two groups ( data not shown).table  2risk of hip fracture with knee arthroplastycases ( % ) controls ( % ) crude or ( 95% ci)adj . or ( 95% ci)(n  =  6,763)(n  =  26,341)never knee arthroplasty6,674 ( 98.7)26,133 ( 99.2)1.00 referent1.00 referentever knee arthroplasty89 ( 1.3)208 ( 0.8)1.69 ( 1.322.18)*1.54 ( 1.192.00)*<2  years before index28 ( 0.4)69 ( 0.3)1.60 ( 1.032.49)*1.43 ( 0.892.29)25  years before index40 ( 0.6)79 ( 0.3)2.01 ( 1.372.96)*1.96 ( 1.312.92)*>5  years before index21 ( 0.3)60 ( 0.2)1.37 ( 0.832.26)1.08 ( 0.631.85)by number of primary ka records before index  one ka record53 ( 0.8)135 ( 0.5)1.54 ( 1.112.12)1.40 ( 1.011.95 )  multiple ka records36 ( 0.5)73 ( 0.3)1.98 ( 1.332.96)1.81 ( 1.202.74)or odds ratio , adj adjusted , ci confidence interval *  statistically significant differences compared to referentadjusted for use of benzodiazepines within 3  months prior , use of bronchodilators , antipsychotics , antidepressants , opioids , antiepileptics , disease - modifying antirheumatic drugs , calcium / vitamin d supplements , a history of anemia , skin or subcutaneous disease , or serious injuries 1  year prior , malignant neoplasms , endocrine disorders , cardiovascular disease , obstructive airway disease , inflammatory bowel disease , musculoskeletal / connective tissue disease ( excluding osteoarthritis ) , or rheumatoid arthritis ever before index datefig
.  1smoothed spline visualization of the relationship between time since first ka and adjusted risk of hip fracture .
as shown in table  2 risk of hip fracture with knee arthroplasty or odds ratio , adj adjusted , ci confidence interval *  statistically significant differences compared to referent adjusted for use of benzodiazepines within 3  months prior , use of bronchodilators , antipsychotics , antidepressants , opioids , antiepileptics , disease - modifying antirheumatic drugs , calcium / vitamin d supplements , a history of anemia , skin or subcutaneous disease , or serious injuries 1  year prior , malignant neoplasms , endocrine disorders , cardiovascular disease , obstructive airway disease , inflammatory bowel disease , musculoskeletal / connective tissue disease ( excluding osteoarthritis ) , or rheumatoid arthritis ever before index date smoothed spline visualization of the relationship between time since first ka and adjusted risk of hip fracture .
adjusted for confounders as shown in table  2 table  3 shows that the increase in risk of hip fracture in patients with ka was highest in patients aged 1870  years ( adj . or  =  2.76 , 95% ci 1.166.59 ) .
the increase in hip fracture risk rapidly decreased toward baseline levels with increasing age ( fig . 
( 95% ci 1.152.57 ) , while the risk was no longer elevated in patients who were older than 80  years ( adj . or  =  1.16 , 95% ci 0.771.75 ) .
the increase in risk of hip fracture tended to be higher in females ( adj . or  =  1.62 , 95% ci 1.222.15 ) compared to males ( adj . or  =  0.82 , 95% ci 0.332.03 ) , although this difference did not reach statistical significance.table  3risk of hip fracture with knee arthroplasty stratified by gender , age and medication usecases ( % ) controls ( % ) crude or ( 95% ci)adj . or ( 95% ci)(n  =  6,763)(n  =  26,341)never knee arthroplasty6,674 ( 98.7)26,133 ( 99.2)1.00 referent1.00 referentever knee arthroplasty89 ( 1.3)208 ( 0.8)1.69 ( 1.322.18)*1.54 ( 1.192.00)*by gender  males7 ( 0.1)24 ( 0.1)1.17 ( 0.502.74)0.82 ( 0.332.03 )  females82 ( 1.2)184 ( 0.7)1.76 ( 1.352.29)*1.62 ( 1.222.15)*by age ( years )  187013 ( 0.2)13 ( 0.0)4.18 ( 1.909.19)*2.76 ( 1.166.59 ) *  718043 ( 0.6)95 ( 0.4)1.82 ( 1.262.63)*1.72 ( 1.152.57 ) *  > 8033 ( 0.5)100 ( 0.4)1.27 ( 0.851.89)1.16 ( 0.771.75)by use of pain relievers 6  months before  yes43 ( 0.6)75 ( 0.3)2.25 ( 1.553.28)*1.93 ( 1.282.91 ) *  no46 ( 0.7)133 ( 0.5)1.37 ( 0.971.92)1.33 ( 0.931.89)by use of oral corticosteroids 6  months before  yes6 ( 0.1)12 ( 0.0)1.94 ( 0.735.18)1.41 ( 0.474.21 )  no83 ( 1.2)196 ( 0.7)1.68 ( 1.292.17)*1.56 ( 1.182.05)*by use of calcium / vitamin d supplements 6  months before  yes7 ( 0.1)18 ( 0.1)1.77 ( 0.734.30)1.40 ( 0.553.58 )  no82 ( 1.2)190 ( 0.7)1.64 ( 1.252.15)*1.56 ( 1.182.06)*or odds ratio , adj adjusted , ci confidence interval*statistically significant differencesadjusted confounders as shown in table  2 compared to referent , except for the stratified covariate of interestopioids ( tramadol or stronger ) , paracetamol , or more than one nsaid prescriptionfig
.  2smoothed spline visualization of the association between first ka and adjusted risk of hip fracture , by age at the index date . dashed lines represent 95% confidence interval bands . adjusted for confounders as shown in table  2 risk of hip fracture with knee arthroplasty stratified by gender , age and medication use or odds ratio , adj adjusted , ci confidence interval * statistically significant differences adjusted confounders as shown in table  2 compared to referent , except for the stratified covariate of interest opioids ( tramadol or stronger ) , paracetamol , or more than one nsaid prescription smoothed spline visualization of the association between first ka and adjusted risk of hip fracture , by age at the index date .
as shown in table  2 ka patients who were dispensed pain relievers ( opioids [ tramadol or stronger ] , paracetamol , or more than one nsaid prescription ) 6  months before the index date did not have a significantly higher risk of hip fracture ( adj . or  =  1.93 , 95% ci 1.282.91 ) compared to patients without a history of pain reliever use ( adj . or  =  1.33 , 95% ci 0.931.89 ) 6  months before ( p  =  0.17 ) ( table  3 ) .
similarly , patients who had used oral corticosteroids in the 6  months before ( adj . or  =  1.41
, 95% ci 0.474.21 ) were at the same risk of hip fracture compared to patients without use of oral corticosteroids in the same period ( adj . or  =  1.56 , 95% ci 1.182.05 ) .
table  4 shows that the association between ka and hip fracture did not substantially change when kas were restricted to patients with a history of oa . the proportion of lower leg oa in patients who had undergone ka was 85% .
ka patients with lower leg oa had the same risk of hip fracture ( adj . or  =  1.45 , 95% ci 1.081.95 ) compared to ka patients without correction of lower leg oa ( adj . or  =  1.54 , 95% ci 1.192.00).table  4risk of hip fracture with knee arthroplasty among osteoarthritis of lower legcases ( % ) controls ( % ) crude or ( 95% ci)adj
. or ( 95% ci)(n  =  6,763)(n  =  26,341)never knee arthroplasty6,674 ( 98.7)26,133 ( 99.2)1.00 referent1.00 referentever knee arthroplasty89 ( 1.3)208 ( 0.8)1.69 ( 1.322.18)*1.54 ( 1.192.00)*by osteoarthritis at any site  never before index12 ( 0.2)21 ( 0.1)2.23 ( 1.104.55)*1.84 ( 0.883.85 )  ever before index77 ( 1.1)187 ( 0.7)1.63 ( 1.242.13)*1.48 ( 1.111.97)*by site of osteoarthritis  lower leg73 ( 1.1)179 ( 0.7)1.61 ( 1.222.12)*1.45 ( 1.081.95 )  < 2  years before24 ( 0.4)61 ( 0.2)1.56 ( 0.972.50)1.39 ( 0.832.32 )  25  years before32 ( 0.5)64 ( 0.2)1.98 ( 1.293.03)*2.00 ( 1.293.11 ) *  > 5  years before17 ( 0.3)54 ( 0.2)1.24 ( 0.722.15)0.93 ( 0.511.69 )  other regions4 ( 0.1)8 ( 0.0)2.00 ( 0.606.64)2.17 ( 0.617.66)or odds ratio , adj adjusted , ci confidence interval *  statistically significant differences compared to referentadjusted for confounders as shown in table  2 risk of hip fracture with knee arthroplasty among osteoarthritis of lower leg or odds ratio , adj adjusted , ci confidence interval *  statistically significant differences compared to referent adjusted for confounders as shown in table  2
this study showed a 1.5-fold increased hip fracture risk in patients who had undergone a ka .
the risk of hip fracture was greatest in young patients ( 1870  years ) . with increasing age , we found a rapid decrease in strength of association , which was no longer elevated in patients aged 81  years and above .
the association tended to be greater during the first few years after surgery , but it did not reach statistical significance .
recent use of pain relievers or glucocorticoids did not alter the overall risk of hip fracture .
this is the second study that has evaluated risk of hip fracture in patients with a history of ka and is in line with the first study , which showed a 58% increased risk of hip fracture in british patients within the first year after their ka .
studies that investigated the association between oa ( the main indication for ka ) and risk of hip fracture have yielded conflicting findings .
some authors suggested a decreased fracture rate among patients with oa [ 57 ] , possibly due to higher bmd levels .
although data are controversial , patients with oa may have increased osteoblastic activity at the oa site , resulting into higher bmd levels and therefore lower fracture rates . on the other hand
, others reported an increased hip fracture risk , which is in line with our study results .
found an increased risk of both vertebral ( 2.0-fold ) and nonvertebral ( 1.5-fold ) fractures in patients with knee
oa . similarly , arden et al .   demonstrated that patients with knee pain or a clinician diagnosis of knee oa have an increased risk of hip and nonvertebral fractures .
this is probably explained by an increased severity of falls since they could not detect an increased number of falls .
it should be noted , however , that data collection on falls is often incomplete .
this could explain the results of a different study that found an increased occurrence of falls among patients with lower limb oa .
furthermore , looking at differences in fracture types , arden et al .   and vestergaard et al
.   found a substantially higher increase in risk of hip fracture compared to other fractures ( such as distal forearm fractures ) .
this may suggest an important role for the nature of falls in patients with knee oa , as explained by arden et al . a us case 
control study has shown that hip fractures tend to result from falling sideways or straight down ( low walking speed ) , whereas forearm fractures may be more likely to be the result of falling backward .
overall , our findings support the studies that found an increased hip fracture risk , indicating that the increased number and severity of falls may attenuate any potentially beneficial effects of higher bmd levels on fracture risk in these patients .
given this proposed mechanism , we would have expected hip fracture rates to decrease after the ka procedure as the surgery relieves pain and partially restores the biomechanical properties of the knee .
one study reported fewer falls within 1  year after the ka , while a recent danish study could not detect any decreases in hip fracture rates during that period . in line with the danish study and
the british study mentioned earlier , we found no obvious decrease in hip fracture risk shortly after the surgery .
a possible explanation for our findings is that patients become rapidly more active after their ka , due to effective knee pain relief .
this could also explain our observed effect modification by age : the youngest patients were at highest hip fracture risk .
compared with elderly patients , these patients may be more likely to increase their physical activity quickly after surgery .
in addition , residual knee pain and stiffness in the first months after surgery may be present in some ka patients and could further explain our observed increased hip fracture risk .
strengths of our study include its population - based setting and that it had a reasonable sample size and longitudinal data collection [ 10 , 1214 ] .
linkage with the dutch national hospitalization registry assured routinely collected ka surgeries and hip fractures .
limitations include the lack of data on physical activity , which could be an alternative explanation for our observed association between ka and hip fracture .
physical activity is significantly increased in ka patients within 9  months postoperatively , while a rapid increase could potentially initiate falls .
in addition , we did not have data on body mass index ( bmi ) , which could have underestimated our observed association between ka and hip fracture .
an increased bmi is a well - known risk factor for knee oa , while it is inversely associated with risk of hip fracture .
nevertheless , our findings are similar to the bmi adjusted results from the general practice research database ( gprd ) study .
similar to the british study , we could not differentiate between the sides of ka or the sides of hip fracture .
this information could be helpful in understanding the mechanism of the observed increased risk of hip fracture following ka .
local bone loss may be induced on the side of the replaced knee , possibly resulting in an increased fracture risk of the hip on the same side . the only feasible way to investigate
this is to link a dedicated joint registry to a hospital / general practitioner database , which has been planned for the uk national joint registry and the gprd .
furthermore , we did not have data on bmd or falling , which could have been useful for the assessment of causality and the underlying mechanism .
frail , unexposed subject bias may have occurred if ka patients had lower mortality rates compared to subjects who had not undergone ka ( due to clinical assessment of operative risk ) .
this was probably not the case : within our control subjects ( those without a hip fracture ) , proportions of cardiovascular hospitalizations were not lower in ka patients ( 6.7% ) compared to patients without a history of ka ( 4.9% ) .
unfortunately , we did not have data on other fracture types ( such as distal forearm fractures ) .
as our data source only keeps track of hospitalizations , fractures other than those of the hip would suffer from underrecording .
although oa diagnosis and ka surgery have not been validated in this data source , we expect high completeness for ka registration .
our hospitalization source was primarily designed to keep track of economic parameters ( e.g. , health - care cost ) . given the high cost of ka surgery , we would expect adequate recording of this procedure . in conclusion
, we showed that ka was associated with a 54% increased risk of hip fracture , which was not influenced by recent use of pain relievers or corticosteroids .
the increase in risk was highest among younger patients ( < 71  years ) , which may reflect a rapid increase in physical activity immediately after surgery .
risk assessment of hip fracture could therefore be considered in patients who are about to undergo a ka .
 the majority of knee arthroplasties ( kas ) are performed in patients with osteoarthritis ( oa ) . 
 although bone mass may be increased in these patients , subjects with knee oa may have an increased risk of hip fracture , possibly due to an increased severity of falls . 
 however , in patients with kas , risk of hip fracture has not been studied extensively . 
 we evaluated the association between kas and hip fracture risk in a population - based case  
 control study using the dutch pharmo record linkage system ( 19912002 , n  =  33,104 ) . 
 cases were patients with a first admission for hip fracture ; controls were matched by age , gender , and geographic location . 
 neither group had a previous history of fracture . 
 time since first ka was calculated . 
 analyses were adjusted for disease and drug history . 
 a 54% increased hip fracture risk was found in patients who underwent ka ( adjusted [ adj . ] or  =  1.54 , 95% ci 1.192.00 ) . 
 we found a strong effect modification by age in these patients : the youngest patients ( aged 1870  years ) were at more increased risk for hip fracture ( adj . or  =  2.76 , 95% ci 1.166.59 ) , while we could not detect a statistical increase in patients aged > 80  years . 
 furthermore , the association tended to be greater during the first few years after surgery , although it did not reach statistical significance . 
 we found that kas are associated with a 54% increased risk of hip fracture , in particular among adult patients aged < 71  years old . 
 fracture risk assessment could be considered in patients who are about to undergo a ka . 