Long-term Results of a Primary End-to-end Anastomosis in Peroperative Detected Bile Duct Injury

The management of a bile duct injury detected during laparoscopic cholecystectomy is still under discussion. An end-to-end anastomosis (with or without T-tube drainage) in peroperative detected bile duct injury has been reported to be associated with stricture formation of the anastomosis area and recurrent jaundice. Between 1991 and 2005, 56 of a total of 500 bile duct injury patients were referred for treating complications after a primary end-to-end anastomosis. After referral, 43 (77%) patients were initially treated endoscopically or by percutaneous transhepatic stent placement (n = 3; 5%). After a mean follow-up of 7 ± 3.3 years, 37 patients (66%) were successfully treated with dilatation and endoscopically placed stents. One patient died due to a treatment-related complication. A total of 18 patients (32%) underwent a hepaticojejunostomy. Postoperative complications occurred in three patients (5%) without hospital mortality. These data confirm that end-to-end anastomosis might be considered as a primary treatment for peroperative detected transection of the bile duct without extensive tissue loss. Complications (stricture or leakage) can be adequately managed by endoscopic or percutaneous drainage the majority of patients (66%) and reconstructive surgery after complicated end-to-end anastomosis is a procedure with relative low morbidity and no mortality.
Introduction
Bile duct injury (BDI) after laparoscopic cholecystectomy (LC) is still a major problem in current surgical practice. BDI is associated with reduced survival, increased morbidity, and poor long-term quality of life (QoL).1,2 The incidence of BDI at laparoscopic cholecystectomy has been reported between 0.3 to 1.4%,3–5 depending on the criteria used to define the injury as well as the study population. Of these injuries, one-third is detected during the procedure.6 Measures to prevent and recognize BDI are outlined in many publications.6–8,9–11 The optimal treatment strategy and short- and long-term outcome has been published extensively.12–14 Controversy exists however about the management of peroperative detected BDI. The most important factor is the extent of tissue loss of the common bile duct, but also severity of inflammation and the size and diameter of the proximal duct. The peroperative management range from simple drainage and referral to a tertiary center to an end-to-end anastomosis (EEA) (duct to duct, with or without T-tube drainage) or a hepaticojejunostomy (HJ).
It has been suggested that EEA is associated with a relative high stricture rate up to 70–80% and consequently a high incidence of secondary repair.15 Therefore, many tertiary centers prefer to perform a HJ instantly. A secondary repair after EEA should be associated with an increased risk of postoperative complications as the formation for strictures and stenosis.16,17 Others, however, consider EEA as a relative simple definitive repair, and also an optimal initial drainage procedure before reconstructive surgery in a secondary setting.18 Reports on large consecutive series to analyze the outcome of EEA are scary because this procedure is generally not performed in referral centers. One should realize that patients referred to such a center after previous EEA elsewhere are a negative selection of the EEA population. So far, a systematic analysis of a large group of patients with an EEA has not been performed and therefore this study was conducted.
The aim of the present study was to analyze short- and long-term outcome in patients who are referred after failure of a primary EEA.
Patients and Methods
Patients Cohort and Data Collection
Between January 1991 and January 2006, 500 consecutive patients were referred to the Academic Medical Center (AMC) in Amsterdam for the management of a BDI after cholecystectomy. Patient data was induced in a prospective database. All types of BDI were included, also minor injuries such as leakage from the cystic duct or ducts of Luschka. To define the location of BDI, the Bismuth classification was used.18 For the present study, the medical charts of all patients who underwent a primary EEA were retrospectively reviewed to analyze the initial operation reports and clinical data.
Data from the referring hospital included: indication for cholecystectomy, type of initial procedure, location of injury, type of repair including the use of a T-tube, the postoperative diagnostic interventions, and the therapeutic interventions before referral. Data from the present center included: symptoms at referral, diagnostic work-up, type of treatment, short-term, and long-term complications.
Endoscopic, Radiological, and Surgical Treatment for complicated EEA
Endoscopic treatment was performed by balloon dilatation or catheter dilatation before stent placement. The biliary stent is placed over the guide wire bridging the stenosis. Two or more stents were inserted if possible. For multiple stent insertion, an endoscopic sphincterotomy was performed to facilitate stent placement. Stents were replaced after 6 weeks and subsequently exchanged every 3 months to avoid cholangitis.
Percutaneous transhepatic catheterization was performed by injecting the contrast medium from the right intercostal approach. A right or left approach for the percutaneous transhepatic biliary drainage was chosen depending on ultrasound images illustrating the biliary anatomy, and the possibility of puncturing a dilated intrahepatic bile duct. Catheterization of intrahepatic bile ducts was performed in standard fashion. A guide wire was advanced through the biliary stricture into the duodenum. When this was achieved, a biliary drainage catheter was inserted. All drainage procedures were performed with the administration of broad-spectrum antibiotics.
In case of a surgical reconstruction, the procedure was performed via a Roux-en-Y hepaticojejunostomy. The stricture in the CBD is transected and the hilar plate is opened. The hepatic ducts of different segmental bile ducts are mobilized and from there opened over the left hepatic duct. Intrahepatic segmental ducts are mobilized and if possible sutured together before one or two jejunal anastomosis are made. A closed suction drain is placed during operation and removed 24–48 hours after surgery. Percutaneous transhepatic drains, when inserted before surgery are left in place and removed after 10 days till 6 weeks, depending on the clinical course, the level of anastomosis and the surgeons’ preference.
Outcome
Follow-up data was obtained through outpatient records and the records of the general practitioner. The outcome of treatment was analyzed by the number complications and late restenosis during follow-up. Failure of treatment was defined as recurrent stenosis after stent therapy followed by surgery or recurrent stenosis after surgical reconstruction followed by additional therapy.
Statistical Analysis
Data from patient characteristics, management, and outcome show descriptive statistics in number of patients and percentages. Mean and median values are given with a minimum and maximum. Long-term stricture-free survival was analyzed by Kaplan Meier Survival Analysis. Data analyses were performed using SPSS® software (SPSS, Chicago, Illinois, USA).
Results
Patients’ Characteristics at Referral
The referral pattern of BDI patients (n = 500) throughout the last 15 years are summarized in Fig. 1. From the total of 500 patients, 56 (11.5%) underwent a primary EEA. Patient characteristics are listed in Table 1. The laparoscopic cholecystectomy (n = 48, 86%) was converted in all patients. An open cholecystectomy was performed in eight patients (14%). In 49 patients (88%), the anastomosis was made over a T-tube. The tube was removed at the referring hospital or at the AMC after a mean of 52 days (range 2–145 days).
Figure 1Referred patients for treatment of bile duct injury. Total number of referred patients (red), patients referred after a primary end to end anastomosis (blue), and patients referred after a primary biliodigestive reconstruction (green).Table 1Patient Characteristics Primary EEAn = 56%Age at cholecystectomyMean (years)52GenderFemale4377Indication for cholecystectomySymptomatic cholelithiasis4580Cholecystitis59Cholecystitis a froid61Type of initial operationOpen procedure814Laparoscopic to open procedure4886Anastomosis over T-tube4988Duration of T-tube in situDays, median (range)42(2–145)
After the primary EEA, 19 patients (34%) underwent other therapeutical interventions before referral (Table 2) (Fig. 2). These patients underwent a range of one to three procedures before referral (median 2). The interventions included a relaparotomy in two patients (4%), percutaneous drainage of fluid collections in five patients (9%), endoscopicially placed stents in 12 patients (21%), a papillotomy in nine patients (16%), and percutaneous transhepatic drainage in two patients (4%). The median interval from the primary EEA to referral was 16 weeks (range 0–141 weeks). At referral, a biliary stricture was diagnosed in 38 patients (68%); in 10 patients (18%), bile leakage was diagnosed and combination of both in eight patients (14%). Symptoms at referral were cholestasis (n = 14, 25%), cholangitis (n = 10, 18%), and abdominal pain (n = 15, 27%). Three patients were referred because of uncontrolled sepsis (n = 2) and peritonitis (n = 1). According to the Bismuth classification, the majority of injuries (leakage of stricture) (n = 47, 84%) was located below the bifurcation. In nine patients (16%), the injury (mostly strictures) involved the bifurcation or the right or left hepatic duct (i.e., Bismuth classification grades IV and V).
Table 2Referral Pattern Primary EEAn = 56%Time interval between injury and referral Weeks, median (range)16 (0–141)Intervention after EEA and before referral Explorative relaparotomy24 Percutaneous drainage59 Endoscopic stenting1221 Endoscopic papillotomy916 PTDa24Symptoms at referral Cholestasis1425 Cholangitis/fever1018 Abdominal pain1527 Abces/biloma47 Uncontrolled sepsis/peritonitis35Diagnosis at referralStenosis3868Leakage1018Combination of stenosis and leakage814Location of injury at referralb  I916  II2138  III1730  IV712  V24aPercutaneous transhepatic drainagebAccording to Bismuth classificationFigure 2ERCP showing successful (aggressive) stent therapy after primary EEA. a Stenosis of the common bile duct. b Stents in situ. c After stent removal within a year.
Management after Referral
Diagnostic work-up was performed by CT-scan (n = 9; 16%), endoscopic cholangiography (n = 38; 68%), and transhepatic cholangiography (n = 9; 16%). The definitive treatment of BDI patients after EEA is shown in the flow diagram (Fig. 3). After work-up, three patients (5.3%) were treated with percutaneous transhepatic cholangiographic drainage (PTCD) and 40 patients (71.4%) were treated endoscopically. Thirteen patients (23%) underwent reconstructive surgery after work-up; eight patients because of a complete stenosis of the CBD, in three patients reconstructive surgery was performed after failure of stent therapy at the referring hospital and in two patients because of a percutaneous fistula and persistent bile leakage.
Figure 3Flow diagram of the success and failure rates after a multidisciplinary treatment of patients who underwent a peroperative end to end anastomosis for bile duct injury. Given percentages are calculated from the number of patients in the previous flow box. PTCD Percutaneous transhepatic catheter dilatation.
Radiological and Endoscopic Treatment
Three patients were successfully treated by PTCD. In two patients, a stenosis was treated by transhepatic dilatation and in one patient, bile leakage was treated by external transhepatic stent insertion.
Forty patients (71.4%) were treated endoscopically (Fig. 2). In 37 patients (66%), stent insertion was successful and in three patients (5%), adequate drainage succeeded by papillotomy. The median number of stent replacements was five (range 1–15) with a median duration of treatment of 359 days (range 39–1,355). Complications occurred in nine patients (24%). Stent dislodgment (n = 3), clogging (n = 2), and cholangitis (n = 5) were mild complications and were successfully treated by stent exchange or administration of antibiotics. One severe complication occurred in a 75-year-old patient. After 4 years of stent therapy, the stent migrated and perforated the duodenum. Finally, the patient died due to multiple organ failure and sepsis.
Surgical Treatment
After referral and during the follow-up period, a new hepatobiliary anastomosis was performed by hepaticojejunostomy in 13 patients (23.2%). Mean duration of hospital stay was 9.1 ± 3.1 days. Postoperative complications occurred in one patient (7.6%) who underwent a PTC procedure after leakage of the anastomosis. No hospital mortality occurred in patients who underwent a reconstructive procedure after a previous EEA.
Long-term Follow-up
After a mean follow-up of 7.1 ± 3.3 years, seven patients (13%) have died. One endoscopically treated patient died due to a complication of treatment as described above. The other patients died due to malignancy (n = 4) and myocardial infarct (n = 2).
The long-term results in patients treated with endoscopic and radiological treatment are as follows: from a total of 43 patients treated with endoscopic or PTCD procedures, 86% (n = 37) was successful. In three patients (7%), signs of restenosis occurred after stent removal after 2, 3.5, and 4 months. Continued stent therapy was successful in all three patients. Five patients underwent reconstructive surgery after prolonged endoscopic stenting. Postoperative complications occurred in two of the five patients and these patients received additional therapy for wound infection (n = 1) and postoperative cholangitis (n = 1).
The long-term results of surgical treatment after EEA are as follows; from 13 patients who underwent a HJ after work-up, a stenosis of the anastomosis occurred in two patients (15%). Both patients underwent successful percutaneous transhepatic dilatation, respectively 9 and 35 months after surgery.
The overall 5 years stricture free survival in the total cohort (n = 56) is 91%, shown by a Kaplan Meier curve in Fig. 4.
Figure 4Kaplan–Meier plot showing proportion of patients without restenosis among 56 bile duct injury patients treated for complications after EEA.
Discussion
The present study describes a selected group of BDI patients, who were referred for treatment after a complicated EEA. This group of patients is a negative selection, representing the worst complications of EEA; otherwise, patients were not referred for additional treatment. So, this study does not provide any information about the success rate of EEA. The present study shows a long-term stricture free survival of 91% in EEA patients after treatment in a tertiary center. The analysis showed that even the majority of complications after primary AEE in a general hospital can successfully be treated by endoscopic and radiological interventions. In only one-third of the patients, a secondary surgical repair is necessary. The surgical reconstruction after EEA was associated with acceptable morbidity and without mortality.
Around 40 to 45 patients are referred annually without any sign of decrease over the last years. Considering 15.000 LC’s per year in the Netherlands, we still consider 0.4–0.5% mentioned in the reviews as an underestimation of the real incidence of BDI, at least in the Netherlands.19 In 20% of the patients referred to the AMC, the injury was detected during the initial surgical procedure. This finding is similar to reports in literature.6,20  From the total of 500 referred BDI patients, 11.2% was referred for the treatment of a complication after peroperative EEA. Because referred patients only represent the complications after EEA, we do not know the real incidence of EEA procedures in BDI.
Peroperative repair in BDI detected during surgery can be performed by EEA (with or without the use of a T-tube) or by a primary HJ. A HJ is a more complex procedure and one should be very careful not to further extend the injury into the intrahepatic ducts or subsequently damage the arterial supply (bleeding and clipping or ligation of right hepatic artery).21,22 The present study shows that if complications occur after EEA, these can successfully be treated by percutaneous or endoscopic balloon dilatation and/or stenting in the majority of patients. A HJ in the acute setting without dilated bile ducts is even more difficult and therefore consulting a surgeon with experience in reconstructive hepatobiliary surgery is recommended. In contrast with a primary HJ an EEA is a relatively simple procedure and can also be performed in less experienced hands. The risk to increase damage is smaller in an EEA procedure and with the use of a T tube instant bile drainage is realized. If indicated, reconstructive surgery by means of an elective HJ can be performed. It is strongly advised to perform a HJ after classification the injury and analyzing the biliary anatomy. Preoperative cholangiography (with the use of the T tube) will illustrate the location of the stenosis and the extension of dilation of the proximal bile ducts. A reconstructive procedure for stenosis of EEA has a satisfying outcome, as peroperative conditions are good after the inflammation has subsided and the bile ducts are dilated due to stenosis.
In a situation in which peroperative bile leakage is due to (extensive) tissue loss, in particular, in patients with more proximal lesions at the bifurcation or intrahepatically, no primary repair should be performed. In this situation, adequate drainage of the upper right abdomen is strongly advised and the patient should be referred for elective reconstruction. Referral to tertiary center in this situation has a positive effect on outcome.2
End-to-end anastomosis is reported to be associated with a high incidence of recurrent jaundice due to stricture formation of the anastomotic area.15 Therefore, some authors suggest that EEA is almost never appropriate if the bile duct has been completely transected,15,23 while others favor this strategy when there is no extensive tissue loss.18 Stent therapy for iatrogenic bile duct strictures has changed during the last decade and therefore the long-term outcome after stenting has improved.24 A more aggressive approach with more stents and smaller time intervals between stent changes is favored. With this new approach, 80% of the patients who undergo an ERCP for postoperative bile duct stenosis, have a 10-year stricture-free survival.25 Although complications occur at a significant rate, these are usually mild. The only severe complication occurred in the present series, due to a migrated stent, was not reported in previous series.24,25 After stent removal, recurrent stenosis develops in 20% of patients within 2 years of stent removal.25 Therefore, endoscopic treatment should be the initial management of choice for postoperative bile duct strictures. Without signs of improvement after endoscopic stenting, reconstructive surgery is indicated in otherwise fit patients.
Of interest is the evaluation of the long-term stricture-free survival after treatment for complications after EEA. After a mean follow-up of 7.1 years, restenosis after treatment developed in 9% of the patients. In all patients who underwent initial endoscopic therapy, restenosis occurred a relatively short time after stent removal, diagnosed within 2 to 8 months follow-up. Therefore, endoscopic treatment is not associated with a high rate of long-term restenosis after stent removal. In two patients, a restenosis occurred within 3 years after a hepaticojejunostomy. Symptoms were cholestasis and cholangitis. In both patients, transhepatic dilatation was successful to resolve the stenosis. The long-term stricture-free survival of 91% in the present series provides evidence for a good outcome after treating complicated EEA patients. If BDI is detected during surgery, in particular if there is no extensive tissue loss, the local anatomy is clear and there is no inflammation, EEA could be considered as a sufficient treatment strategy. Patients with postoperative complications (stricture or leakage) should be treated by a multidisciplinary team of gastroenterologists, radiologists, and surgeons. Postoperative complications can adequately be managed by endoscopic or percutaneous drainage in two-third of the patients. Reconstructive surgery after a complicated EEA is associated with low morbidity and no mortality.

end-to-end anastomosis
bile duct injury
cholecystectomy


Loss of treatment benefit due to low compliance with bisphosphonate therapy

Summary Among 8,822 new female bisphosphonate users, non-compliant bisphosphonate use was associated with a 45% increased risk of osteoporotic fracture compared to compliant use (MPR ≥80%). Classifying compliance into five categories, fracture risk gradually increased with poorer compliance. These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit.
Introduction
Osteoporosis is a systemic condition characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and, consequently, an increased fracture risk [1]. Osteoporosis has clinical and public health importance because osteoporotic fractures are one of the most common causes of disability and a major contributor to medical costs in many regions of the world [2]. Bisphosphonates are potent inhibitors of the osteoclast-mediated resorption of bone and widely used to treat osteoporosis and reduce the risk of osteoporotic fractures [3].
Long-term therapy with bisphosphonates is required to realise the full benefits of this treatment [3, 4]. This is supported by a recent PHARMO study that showed that the risk of fractures was reduced by 26% after one year persistent bisphosphonate use and up to 32% after two year persistent use [5]. However, in daily clinical practice, 50% to 75% of patients discontinue bisphosphonate use already in the first year of therapy [5–8]. Moreover, non-compliance with bisphosphonates has also been reported to be a frequent issue, with rates varying from 35% to 65% [6, 9]. Reasons for low compliance with bisphosphonate treatment are the stringent regimen to minimize the risk of oesophageal irritation, the existence of drug-related gastrointestinal side effects, and the fact that osteoporosis is often asymptomatic in early stages [10]. Caro et al. showed that patients who were compliant with their osteoporosis medication, including bisphosphonates, estrogens and calcitonin, experienced a 16% lower fracture rate compared to non-compliant users [11]. The objective of this study was to investigate the risk of osteoporotic fractures associated with low compliance with bisphosphonates in more detail. In addition to dichotomizing compliance, we also classified compliance into five categories.
Patients and methods
Setting
Data were obtained from the PHARMO Record Linkage System (PHARMO RLS) which includes several databases, among which drug dispensing and hospitalization data of more than two million residents of the Netherlands. The drug dispensing histories contain data on the dispensed drug, the type of prescriber, the dispensing date, the amount dispensed, the prescribed dose regimens, and the duration of use. All drugs are coded according to the Anatomical Therapeutic Chemical (ATC) Classification. The hospital records include detailed information concerning the primary and secondary diagnoses, procedures, and dates of hospital admission and discharge. All diagnoses are coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).
Study cohort
The source population included all new users of bisphosphonates in the period from January 1999 until July 2004. These patients were not dispensed any anti-osteoporotic drugs (bisphosphonates, raloxifene, tibolone, estrogens, hormone replacement therapy, calcitonin or teriparatide) for at least one year before their first bisphosphonate dispensing. All female new users of alendronate (10 mg daily or 70 mg weekly) or risedronate (5 mg daily or 35 mg weekly) (i.e. the dosages indicated for the prevention or treatment of postmenopausal osteoporosis), aged ≥45 years or with diagnosed postmenopausal osteoporosis (ICD-9-CM code 733.01), without gaps in registration in PHARMO RLS, and with a registration of at least one year before and one year after starting bisphosphonate treatment were included in the study cohort.
All study patients were followed from the first bisphosphonate dispensing until the occurrence of the outcome of interest, death, end of registration in PHARMO RLS or end of the study period, whichever event was earliest.
Compliance
Compliance with bisphosphonates during follow-up may change and was measured over 90-day intervals using the Medication Possession Ratio (MPR). MPR was defined as the sum of days’ supply of all alendronate and risedronate dispensings during or overlapping the 90-day interval divided by 90 potential days of bisphosphonate therapy. For each dispensing only the days’ supply covering a specific interval were counted. E.g. of a 100-days supply dispensed at follow-up day 60, only 30 days were counted when calculating the MPR over the first interval (day 0–90) and 70 days for the MPR over the second interval (day 91–180). The maximum value of a MPR was set at 1. Subdividing follow-up in larger intervals was assumed too rough and subdividing in smaller intervals was not feasible regarding the usual prescription length of 90 days.
Osteoporotic fractures
The outcome variable osteoporotic fracture was defined as hospitalisation for an osteoporotic fracture during follow-up. Hospitalisations were selected based on primary discharge diagnosis for probable (ICD-9-CM codes 805.2 (vertebral thoracic), 805.4 (vertebral lumbar), 820 (proximal femur), 812 (proximal humerus), 813.4 (distal radius/ulna), 814 (carpus)) or possible (ICD-9-CM codes 823.0 (proximal tibia/fibula), 807.0 (rib), 807.2 (sternum), 808.0 (pelvis)) osteoporotic fractures.
Covariates
For all patients, a history of osteoporotic fracture was assessed. Furthermore, we determined use of non-steroidal anti-inflammatory drugs, analgesics, benzodiazepines and antidepressants in the year after starting bisphosphonate treatment as these drugs are associated with an increased risk of fractures [12–14]. Similarly, we assessed use of thiazide diuretics, ß-blockers and statins in the year after start as these drugs are associated with a reduced risk of fractures [15–17].
Statistical analyses
The association between low compliance with bisphosphonates and the risk of fractures was analysed univariately and multivariately using time-dependent Cox regression analysis to account for changing compliance over time. In this analysis, at the time of each fracture, the cumulative compliance up to and including the corresponding 90-day interval of women who had experienced a fracture was compared to the cumulative compliance of those women who remained fracture-free at this time. The cumulative compliance of the fracture-free patients was measured up to the interval of corresponding fracture.
In a first analysis, compliance was dichotomized and a MPR <80%, i.e. non-compliant bisphosphonate use was compared to a MPR ≥80%, i.e. compliant use. In a second analysis, compliance was classified into five categories: <20%, 20–49%, 50–69%, 70–89% and ≥90% (reference). A Wald test for trend was performed. Assuming that the effect of bisphosphonates is not immediate, and in line with Caro et al. [11], fractures occurring in the first 182 days of follow-up were excluded from the analyses. In a sub-analysis, this exclusion period was varied. Furthermore, an additional analysis was performed excluding women with only one bisphoshonate dispensing during follow-up; in these patients it is less sure that they actually used the drug.
The multiple regression models included age, history of fracture and all covariates that were univariately associated with the risk of fractures and significantly contributed to the multivariate model, i.e. inclusion of the covariate resulted in a change of the compliance hazard ratio (HR) of 5% or over, starting with the most potent covariate. HRs and 95% confidence intervals (CI) were estimated using SAS V8.2 UNIX (Cary, NC, USA).
Results
The study cohort included 8,822 new female users of daily or weekly alendronate or risedronate, who contributed a total of 22,484 person-years of follow-up during the study period. More than half of the patients were older than 70 years of age (n = 4,708, 53%) and about one quarter of the patients used corticosteroids (irrespective of quantity) (Table 1). The first bisphosphonate was mainly prescribed by the general practitioner (64%). Only 197 patients (2%) were hospitalized for an osteoporotic fracture in the year before starting treatment.
Table 1General characteristics of new bisphosphonate users between 1 January 1999 and 30 June 2004 (N = 8,822)CharacteristicN%Age class (years)45–5488910.155–693,22536.5≥704,70853.4Mean age (years) ± sd 69.4 ± 10.3Year of start1999 / 20002,25025.52001 / 20022,76931.42003 / 20043,80343.1Initial bisphosphonateDaily bisphosphonate4,22247.9Weekly bisphosphonate4,60052.1First prescriberGeneral practitioner5,70464.7Internist, rheumatologist, orthopedist2,31326.2Other prescribers8059.1Hospitalization for an osteoporotic fracture in the year before start 1972.2Use of corticosteroids in the year before start (irrespective of quantity)2,38927.1Follow-up time (months)12–232,93933.324–352,26825.7≥363,61541.0
During follow-up, 216 patients (2%) experienced an osteoporotic fracture, of which 40 patients during the first six months and 78 during the first year. About two third of all osteoporotic fractures were located at the proximal femur.
The percentage of patients with a MPR < 80% (i.e. non-compliant patients) increased from 34% (3,018/8,822) after six months of follow-up to 42% (3,743/8,822) after one year, 51% (3,014/5,883) after two years and 60% (2,149/3,615) after three years of follow-up. Subdividing MPR in classes (Fig. 1), the majority of patients either had a MPR ≥90% or a MPR <20%, with the first group decreasing and the latter group increasing over time.
Fig. 1Compliance with bisphosphonates, classified in five MPR categories, after six months, one year, two years and three years of follow-up. MPR: medication possession ratio
Dichotomizing compliance, a MPR <80%, i.e. non-compliant bisphosphonate use was associated with a 40% increased risk of osteoporotic fracture more than six months after starting treatment (HR 1.41 95% CI 1.04–1.91, adjusted for age and history of fracture (see Table 2 for association between co-variates and fracture risk)) compared to a MPR ≥80%, i.e. compliant use. Varying the exclusion period, i.e. excluding fractures occurring in the first year of follow-up or including all fractures during follow-up, yielded similar adjusted increased risks (HR 1.50; 95%CI 1.06–2.13 and HR 1.45; 95%CI 1.10–1.91, respectively). Excluding women who received only one bisphosphonate dispensing during follow-up also did not change the results (adjusted HR 1.45; 95% CI 1.05–1.99, based on 156 fracture patients and 7,758 fracture-free patients).
Table 2Association between co-variates and fracture risk more than six months after starting treatment Fracture patients (N)Fracture-free patients (N)N%N%HRcrude95% CITotal1761008,606100Age (years) at start 45–5474.087910.21.00reference 55–692916.53,18937.11.160.51–2.66 ≥7014079.54,53852.74.282.00–9.15Year of start 1999/20008648.92,15825.11.681.04–2.71 2001/20026335.82,69131.31.550.97–2.49 2003/20042715.33,75743.61.00referenceHistory of osteoporotic fracture52.81902.21.520.63–3.70Comedication in the year after start1 Analgesics6838.62,13624.81.821.34–2.46 Benzodiazepines8045.53,32438.61.300.96–1.74 Antidepressants2916.51,04612.21.521.02–2.26 ß-blockers4726.71,92922.41.350.97–1.89HR: hazard ratio, CI: confidence interval1 Univariate non-significant comedications (i.e. non-steroidal anti-inflammatory drugs, thiazides and statins) are not shown.
Classifying compliance into five categories, fracture risk gradually increased with poorer compliance (p-value <0.05 for trend). Compared to a MPR ≥90%, the adjusted risk of fracture increased from 1.2 times for a MPR between 50% and 90% to 1.8 times for a MPR less than 20% (Fig. 2).
Fig. 2The relationship between compliance with bisphosphonates, classified in five MPR categories, and fracture risk more than half a year after starting treatment. HRs are adjusted for age and history of fracture and are compared to a MPR ≥90%. MPR: medication possession ratio, HR: hazard ratio, CI: confidence interval
Discussion
This study indicates that non-compliant bisphosphonate users had an approximately 50% higher likelihood of osteoporotic fracture compared to compliant users. Classifying compliance into five categories, fracture risk gradually increased with poorer compliance to an 80% risk increase with very low compliance compared to very high compliance. These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit.
To quantify the loss of treatment benefit with low compliance, information on fracture risk in women not treated with bisphosphonates is necessary. The above mentioned percentage risk increases are compared to compliant use and cannot be translated into percentage loss of treatment benefit. We chose not to use untreated patients as reference because of the heterogeneity of patterns of treatment use that exist within this group. In a meta-analysis of 11 trials of alendronate for the treatment of postmenopausal osteoporosis, a consistent 50% reduction in fracture risk was seen compared to placebo [18]. For risedronate, a meta-analysis of 8 trials revealed a 25 to 35% reduction in fracture risk compared to placebo [19]. In other words, untreated women are 1.5 to 2 times as likely to experience a fracture compared to women using bisphosphonates. Assuming that the patients with a MPR ≥90% in our study are comparable to the treated patients in trials, the 1.6 to 1.8 times increased fracture risk we observed with a MPR <50% can be translated into a 80 to 100% loss of treatment benefit. Apparently, patients with the lowest compliance are essentially comparable to non-treated patients.
At present, in addition to Caro et al., others have reported on the relationship between compliance with bisphosphonates and fracture risk [11, 20, 21]. Siris et al. [20] found a relative fracture risk reduction of 25% with compliant use of alendronate or risedronate, i.e. a 33% risk increase with non-compliant use. There was a progressive relationship between compliance and fracture risk reduction, commencing at a MPR around 50% and becoming more pronounced at a MPR ≥75%. This finding, like our results, suggests that low-compliant patients gain only marginal benefit from bisphosphonate therapy. Among women starting drug therapy for osteoporosis (of which two-third bisphosphonates) Weycker et al. [21] found that compared to women with a MPR <30%, the odds of fracture was similar (1.02) for women with a MPR between 30 and 69% and women with a MPR between 70 and 89%, but lower (0.70) for women with a MPR ≥90%. The latter corresponds to a 1.4 times increased risk of fracture with a MPR <30% compared to a MPR ≥90%. Caro et al. [11] reported that compared to a MPR >90%, fracture risk was significantly increased at lower compliance levels, i.e. up to 1.4 times with a MPR ≤50%. However, it is not clear whether this effect was gradual. In a study population of mainly users of hormone replacement therapy, Huybrechts et al. [22] found that compared to women with a MPR ≥90%, fracture risk was similar (HR 1.09) for women with a MPR between 80 and 90%, but higher for women with a MPR between 50 and 80% and women with a MPR <50% (HR 1.18 and 1.21, respectively). Our associations are about similar than reported by Siris et al., but stronger than found by Caro et al., Weycker et al. and Huybrechts et al. The most likely explanation for this is that our and Siris’ study population was restricted to bisphosphonate users, while the others also included users of other, less potent anti-osteoporotic drugs (30% to 65% of the study population).
There is a previous PHARMO study on bisphosphonate use and risk of fractures, using persistence [5]. Besides a different measure of drug exposure, the current study differs from this previous study in that the study period was extended, different inclusion criteria were applied and new patients were included besides previously studied patients. Although persistence and compliance are measured differently, with persistence referring to the duration of uninterrupted drug use, they are closely related. Patients classified as non-compliant would also have been classified as non-persistent and vice versa. The results of our current study are in line with our previous study in which the risk of fractures was reduced by 26% after one year persistent bisphosphonate use and up to 32% after two years of persistent use [5]. Similarly, Gold et al [23] reported that persistent bisphosphonate use for at least 6 months was associated with a 26% lower fracture risk. Expressing these results the other way around, non-persistent bisphosphonate use is associated with an about 40% fracture risk increase. Among a population of mainly users of hormone replacement therapy, one year of uninterrupted therapy reduced the likelihood of fractures with significant odds ratios of 0.38 for hip fractures and 0.60 for vertebral fractures [7].
Our analyses may be limited by some issues common to observational database research in daily clinical practice. Most importantly, although we considered a large number of known confounders in our analyses, including history of fractures, there may be other confounding factors for which information was not available, such as bone mineral density (BMD). BMD is an important determinant of fracture risk [24] and BMD testing has been shown to be positively associated with persistence and compliance [25, 26]. Consequently, the results of our analyses are likely to be conservative in the sense that compliant patients may have had an increased fracture risk because of low BMD, and history of fractures only partially controlled for this. Furthermore, it is possible that patients have started using other anti-osteoporotic drugs, e.g. raloxifene, during follow-up and stopped bisphosphonate use. This means that part of the patients who were non-compliant with bisphosphonates may have been protected against fractures by another anti-osteoporotic drug and the observed increased fracture risk with non-compliant bisphosphonate use therefore may be underestimated. However, we know from our database that this concerns only about 7% of patients in the first year of bisphosphonate treatment. In addition, compliance with treatment was based on dispensing data. As it is unknown whether a patient actually used the drug, compliance may have been overestimated. However, it seems likely that patients who obtain prescription refills do take their medication. Excluding women who filled only one bisphosphonate dispensing during follow-up from the analyses did not change the results. Another limitation relates to the classified analysis. With the use of five compliance categories studying a trend is possible but it does not give information on the point at which there is a significant shift in fracture risk. Ideally, 10% MPR categories should be used. However, patient numbers per 10% MPR categories (data not shown) did not allow for this detailed analysis.
To increase the treatment benefit of bisphosphonates, compliance should be improved. Related to the inconvenient, stringent intake regimen, dosing frequency is an important determinant of compliance with bisphosphonates. In recent earlier studies, once-weekly dosing was associated with better compliance and persistence compared to daily dosing. However, even with the weekly regimen, compliance and persistence were suboptimal in about half of the patients [6, 8, 9]. Bisphosphonates with less frequent dosing regimes than weekly, e.g. monthly or three-monthly ibandronate or annual zolendronate, are either available yet or upcoming and may further improve compliance and therefore treatment benefit. In a cross-over trial, women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy and found it more convenient than once-weekly alendronate therapy [27]. There are no data yet on the actual impact of this once-monthly, and other formulations on compliance with bisphosphonate therapy and reduction of fracture risk in daily practice. Other keys to improve compliance are e.g. healthcare provider - patient communication and continuous reinforcement of the importance of treatment. Reminder systems may help the patient comply with therapy, especially with infrequent dosing regimes. However, results from a review show that current methods of improving patient compliance for several chronic health problems are mostly not very successful [28]. Furthermore, although a number of demographic and clinical variables are associated with compliance with bisphosphonates these predictors, either individually or together, have been shown to have low predictive value for identifying patients who will become non-compliant [25].
In conclusion, the results of this study show a statistically significant association between level of compliance with bisphosphonates and level of fracture risk, emphasizing the importance of treatment compliance in obtaining maximal bone protection.

benefit bisphosphonates non-compliance fracture osteoporosis


Whole-body imaging of the musculoskeletal system: the value of MR imaging

In clinical practice various modalities are used for whole-body imaging of the musculoskeletal system, including radiography, bone scintigraphy, computed tomography, magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT). Multislice CT is far more sensitive than radiographs in the assessment of trabecular and cortical bone destruction and allows for evaluation of fracture risk. The introduction of combined PET-CT scanners has markedly increased diagnostic accuracy for the detection of skeletal metastases compared with PET alone. The unique soft-tissue contrast of MRI enables for precise assessment of bone marrow infiltration and adjacent soft tissue structures so that alterations within the bone marrow may be detected before osseous destruction becomes apparent in CT or metabolic changes occur on bone scintigraphy or PET scan. Improvements in hard- and software, including parallel image acquisition acceleration, have made high resolution whole-body MRI clinically feasible. Whole-body MRI has successfully been applied for bone marrow screening of metastasis and systemic primary bone malignancies, like multiple myeloma. Furthermore, it has recently been proposed for the assessment of systemic bone diseases predisposing for malignancy (e.g., multiple cartilaginous exostoses) and muscle disease (e.g., muscle dystrophy). The following article gives an overview on state-of-the-art whole-body imaging of the musculoskeletal system and highlights present and potential future applications, especially in the field of whole-body MRI.
Introduction
The skeletal system is a frequent target of metastatic spread from various primary tumors like carcinoma of the breast, lung and prostate cancer. Moreover, primary malignancies may also originate from the bone marrow, such as lymphoma and multiple myeloma [1]. Therefore, it is highly important to accurately assess manifestations of malignant diseases within the bone marrow in order to facilitate adequate therapy and predict prognosis.
Only pronounced destruction of bone with loss of bone mineral content exceeding 50% is readily visible in radiographic examinations [2]. Computed tomography (CT) is definitely more sensitive than radiography and it is the image modality of choice to evaluate the extent of destruction of trabecular and cortical bone and to assess stability and fracture risk. Magnetic resonance imaging (MRI), on the other hand, allows bone marrow components, such as hematopoietic and fat cells, to be visualized. Moreover, tumor infiltration into the spinal canal and paravertebral soft tissues is clearly depicted. Compared with other imaging modalities like radiography, CT or bone scintigraphy, it is the most sensitive technique for the detection of pathologies restricted to the bone marrow, even if trabecular bone is not destroyed [3, 4]. It has been reported that up to 40% of skeletal metastases occur outside the field of view covered by a routine assessment of the axial skeleton, underlining the importance of whole-body bone marrow imaging [5]. In the past, different requirements for patient positioning and coil set-up complicated the introduction of MRI as a practicable whole-body application. With multi-channel whole-body MRI (WB-MRI) scanners, however, head-to-toe assessment of the whole skeletal system has become a realistic option without compromises in image quality compared with dedicated examinations of limited anatomical areas. Beyond the assessment of malignant bone neoplasms, WB-MRI has recently been proposed for the whole-body imaging of systemic muscle disease and may prove useful for an evidence-based screening of patients suffering from diseases that predispose to bone malignancy (e.g., multiple cartilaginous exostoses).
Technical aspects of whole-body MRI
Due to its lack of ionizing radiation MRI seems suitable for whole-body imaging, but for a long time its primary application has been the assessment of focal pathologies within particular organs and body parts. The most severe challenges of WB-MRI in the past have been long examination times, mainly caused by time-consuming patient repositioning and changing of the array configuration. Initially, the sequential scanning approach for WB-MRI of the skeletal system consisted of separate scanning steps of T1-weighted and STIR (short tau inversion recovery) imaging at five body levels with at least one patient repositioning process using conventional head, neck, body, and spine array coils. For a complete whole-body examination, including dedicated imaging of the spine in sagittal orientation, a total room time of at least 60 min had to be taken in account. Steinborn et al. introduced for the first time this whole-body bone marrow scanning concept for the screening of bone metastases and, despite the considerable complexity of the examination, reported advantages in diagnostic accuracy for MRI compared with conventional WB imaging techniques, like skeletal scintigraphy [6]. Later, attempts to overcome FOV restrictions and increase patient comfort were based on a rolling platform concept mounted on top of the scanner table, making the patient glide in between a “coil sandwich” comprised of the body coil and the integrated spine coil (AngioSURF™/BodySURF™; MR-Innovation, Essen, Germany). However, with this approach considerable compromises in spatial resolution, especially in peripheral body regions like the head/neck and lower extremities, had to be tolerated [7]. With the introduction of multi-channel MR scanners, using a system of multiple phased array coils covering the whole body like a matrix, imaging of the total skeletal system without compromises in spatial resolution became possible. In particular, the combination of free table movement with parallel imaging acquisition techniques (PAT) resulted in substantially shorter room time and allowed to integrate otherwise time-consuming, but indispensable sequence types for bone marrow imaging (e.g., STIR sequences). The proposed imaging protocol for high resolution T1-weighted turbo spin echo (TSE) and STIR imaging from head to toe is performed with 1.3 × 1.1-mm and 1.8 × 1.3-mm plane resolution respectively (5-mm slices, matrix 384, PAT 2–3). Additionally, dedicated T1-weighted TSE and STIR imaging of the complete spine is performed (1.0 × 1.0-mm plane, 3-mm slices, matrix 384), which results in a total scan time of 43 min.
A promising new concept for WB-MRI is the continuously moving table technique with the use of PAT. Recently, a SENSE reconstruction algorithm has been successfully applied on stationary receiver coils with arbitrary coil dimensions for continuously 3D gradient echo imaging of the complete body without significant constraints in image quality [8]. Zenge et al. have reported promising initial results for 3D whole-body continuous data acquisition using the rolling table concept as a new potential strategy for WB-MRI metastases screening, especially for large field-of-view imaging in short bore systems [9].
Technical aspects of whole-body CT
Multislice CT (MS-CT) is frequently used in oncologic imaging, and in the detection of bone destruction CT is far more sensitive than radiography [10]. Moreover, it is unique in its ability to evaluate the extent of osseous destruction and to assess stability and fracture risk [11]. Whole-body imaging usually implies CT of the neck, thorax, abdomen/pelvis in axial orientation with multi-planar reconstructions and recalculation of bone window setting. Continuous hardware improvements for CT imaging from single-slice scanners to 64-slice scanners have resulted in larger FOV and faster acquisition times with high resolution. Examination time now is reduced to 1–2 min and improvement in resolution with the resulting formation of isotropic voxels allows high quality multiplanar reconstructions. In particular, the use of ultrathin collimation (0,5 mm) can provide excellent image quality for the neck and peripheral skeleton. Furthermore, with automated tube current dose modulation systems exposure of the patient to ionizing radiation could be reduced by 10–68% on average, depending on the anatomical region, without substantially sacrificing image quality [12]. Absolute dose reduction (described as volume CT dose index) ranges from 11.97/8.18 mGy for a pelvic examination to 23.28/7.45 mGy when a combined angular and z-axis modulation system is used.
Multislice CT enables bone destruction to be detected as well as osteoblastic and mixed patterns with osteosclerosis and destruction. In cases of diffuse bone marrow infiltration inhomogeneous osteoporosis may be detected. However, as in radiography, this may mimic osteoporosis, unless areas of bony destruction are present. 3D reconstruction algorithms, like VRT (volume rendering technique), can be used to display complex fractures (e.g., pathological fracture) and further increases the reliability to detect occult vertebral fractures compared with plain radiographs. Furthermore, the 3D morphology of vertebral fractures may give indications concerning the nature of the fracture (e.g., tumorous vs. osteoporotic fracture).
Clinical application of whole-body MRI
Whole-body MRI is increasingly used in the field of oncologic imaging as an adjunct or alternative to established multi-modality approaches (e.g., radiographs, MS-CT, ultrasound, scintigraphy) for initial tumor staging or screening for tumor recurrence after curative therapy. Promising results have been reported for the detection of distant metastatic disease, especially in tumors that frequently metastasize to the bone, liver, and brain (Fig. 1) [13, 31]. Recently, WB-MRI has been proposed as a sensible application for a more integrated assessment of multiple myeloma and systemic muscle diseases [16, 17, 18, 19].
Fig. 1A 60-year-old patient with a malignant melanoma. a Coronal T1-weighted turbo spin echo (TSE) whole-body (WB) magnetic resonance imaging (MRI) indicates multifocal metastatic disease of the liver (arrow). b Whole-body positron emission tomography-computed tomography (PET-CT) shows multiple areas of pathologic [18F]-fluorodeoxyglucose (FDG)-uptake in the right atrium (arrow), the liver (arrowheads), and in the right iliac bone (arrowhead). c Contrast-enhanced CT reveals a metastasis within the right atrium. d T1-weighted TSE WB-MRI confirms a hypointense lesion in the right iliac bone indicating bone metastasis. e Axial fat-saturated contrast-enhanced MRI of the pelvis shows another bone metastasis in the right sacral bone (arrow). f, g The corresponding CT images in the bone window setting show extensive osteolysis within the right iliac bone; however, no morphologic changes are found in the right sacral bone
Metastasis
Based on morphological criteria in radiography, CT, and MRI, skeletal metastases are classified as osteolytic (approximately 50%), osteoblastic (35%) ,and mixed type (15%). For MRI bone screening, the combination of unenhanced T1-weighted spin echo and turbo-STIR sequences proved to be highly sensitive in discriminating benign from malignant marrow disorders [20]. On T1-weighted sequences tumor spread is identified by replacement of normal fat containing marrow, resulting in a hypointense signal . Fat-suppressed sequences, such as STIR, depict neoplastic lesions by virtue of the hyperintense signal due to increased content of water within the tumor cells (Fig. 2). However, osteoblastic metastases may be depicted in STIR sequences with variable signal intensities from hypointense in dense sclerotic lesions to hyperintense when more cellular components are present [21]. The unique soft-tissue contrast of MRI allows precise assessment of tumor infiltration within the bone marrow and even diffuse infiltration of the bone marrow with neoplastic cells, not associated with focal bone destructions or formation of new bone, is detected [22]. In some cases additional sequences, such as dynamic studies of signal enhancement after gadolinium injection, may be performed for accurate differentiation from benign bone marrow changes, such as hyperplastic bone marrow formation [23]. Finally, MRI allows for precise assessment of adjacent paraosseous structures, such as the spinal canal.
Whole-body MRI compared with bone scintigraphy
In clinical practice multi-modality algorithms are most commonly used when metastatic bone disease is suspected. They include radiography, bone scintigraphy, PET, CT, and MRI. In many institutions 99mTc-phosphonate-based bone scanning is performed as the method of initial bone marrow screening. However, scintigraphy provides only limited spatial resolution and at an early stage of disease lesions may remain invisible in the absence of an osteoblastic response [24]. Furthermore, misinterpretation of tracer uptake in healing fractures or degenerative disease may lead to false-positive findings. The diagnostic performance of MRI compared with bone scintigraphy for the detection of skeletal metastases has been examined in various studies and higher specificity and sensitivity in the early detection of skeletal metastases have been reported [6, 24, 25]. Steinborn et al. compared combined T1-weighted and STIR WB-MRI with bone scintigraphy using the sequential scanning approach in a lesion-by-lesion analysis [6]. WB-MRI reliably detected more confirmed skeletal metastases (91%) than bone scintigraphy (85%). Another study group reported higher sensitivity and specificity of WB-MRI (92%/90%) compared with scintigraphy (83%/80%) on a patient-by-patient basis [20]. Daldrup-Link et al. analyzed both methods for the detection of bone metastases in 39 children and young adults and observed a higher sensitivity of 82% for WB-MRI compared with 71% for scintigraphy, with this difference increasing, especially in medium-sized lesions between 1 and 5 cm [3].
Interestingly, both methods showed differences in performance according to lesion location. Most false-negatives in scintigraphy were found in the spine, while diagnostic problems for WB-MRI occur in the thoracic cage and skull, especially when coronal imaging orientation is used, a problem that is certainly increased by motion artefacts. These problems might be overcome when using fast turbo spin echo sequences for thoracic imaging in combination with axial slice orientation.
Whole-body MRI compared with MS-CT
Multislice CT is far more sensitive than radiography in the assessment of focal bone destructions. Krahe et al. compared radiography and CT examinations in 112 patients with metastases of the spine [10]. MS-CT identified 268 involved vertebrae while radiography depicted 88% of these lesions when the vertebral body was involved and only 66% when other parts of the vertebrae were affected. Intraspinal and paravertebral tumor extension was correctly assessed by plain radiography in only 23% and 33% of cases respectively. Recently, multidetector MS-CT has been proposed for whole-body screening of the skeletal system as an alternative to bone scintigraphy [26]. Groves et al. investigated 43 patients with suspected bone metastases using bone scintigraphy and 16-detector MS-CT and detected metastatic disease in 14 out of 43 and 13 out of 43 patients respectively, with an agreement of 84%, suggesting a similar diagnostic performance of both modalities. The authors concluded that in case of suspected skeletal metastasis, scintigraphic studies may not be needed, when an adequate whole-body MS-CT tumor staging with recalculation of bone window setting has been performed. Consecutively, this might shorten diagnostic pathways and save resources. However, it is not yet clear whether MS-CT is equal to MRI for the assessment of bony metastases. First results have demonstrated the superior detection rate of MRI (Fig. 1) [27].
Whole-body MRI compared with PET-CT
In contrast to MRI and MS-CT, positron emission tomography (PET) using [18F]-fluorodeoxyglucose (FDG) provides functional information by tracing increased FDG uptake directly into the tumor cells. Recent studies indicate that whole-body FDG-PET increases specificity of bone screening compared with bone scintigraphy, although there is conflicting evidence whether there is a significant gain in sensitivity [28]. Still, FDG is a tracer that is not tumor-specific and may also accumulate in the presence of inflammation and thus lead to false-positive findings. Also, FDG is not suitable for several tumor entities due to poor tracer uptake, e.g., prostate cancer, myxoid tumors of the gastrointestinal tract, low-grade sarcomas or renal cell carcinomas [29]. A clear technical disadvantage of PET, similar to scintigraphy, is its poor anatomical resolution, which often makes the exact localization of a lesion difficult. Fused PET-CT scanners combine the functional data of PET with the detailed anatomical information of MS-CT scanners in a single examination and have further improved diagnostic accuracy. Various authors have reported a significant decrease in ambiguous lesions and an improvement in the specificity of PET-CT compared to that of PET alone in the detection of malignant disease [14, 30].
Only a few study groups have directly compared the performance of WB-MRI with FDG-PET-CT in the detection of skeletal metastases [15, 31]. Antoch et al. analyzed the accuracy of both modalities in 98 patients in terms of TNM-based tumor staging. Both imaging procedures revealed a similar diagnostic sensitivity to the detection of distant metastases (WB-MRI  93%, PET-CT 94%). Regarding bone metastases, the sensitivity was significantly higher when using WB-MRI (85%) instead of PET-CT (62%). Our own observations confirm these data. We examined 41 patients with suspected skeletal metastases with both FDG-PET-CT and WB-MRI using a multi-channel scanner with PAT [31]. In a lesion-by-lesion analysis 102 malignant and 25 benign bone lesions were confirmed by histology or follow-up. WB-MRI showed a significantly higher diagnostic accuracy than PET-CT (91% vs. 78%, Figs. 1, 2). In particular, lesions smaller than 5 mm were visualized by WB-MRI with a cut-off size of 2 mm for WB-MRI compared with 5 mm for PET-CT. Lesions less than double the size of the spatial resolution of the PET scanner (usually 6 mm) can especially lead to false-negative results. Additionally, 10 bone metastases in distal parts of the body were revealed by WB-MRI due to the larger field of view (the FOV of a routine PET-CT is restricted to the diagnostic spiral CT, usually ranging from the skull base to the proximal femora). However, specificity was higher in PET-CT (PET-CT 80% vs. WB-MRI 76%). Here, certainly, the additional metabolic information of PET plays the most important role in reliably discriminating between malignant and benign lesions (e.g., atypical haemangioma) [32].
Fig. 2A 28-year-old man with non-Hodgkin’s lymphoma. a Coronal whole-body STIR imaging shows suspect areas with hyperintense signal in the right clavicular region and both iliac bones. b Magnification shows a mass extending from the right clavicular fossa and infiltrating the right apical thoracic cage. c The lesion shows a pathological FDG uptake in PET-CT, indicating malignancy. d The T1-weighted sagittal image of the spine shows extensive multifocal lymphoma manifestations. e PET-CT underestimates the degree of tumor involvement by showing tracer uptake only in the thoraco-lumbar region
On the other hand, at least in breast cancer, different patterns of FDG uptake have been reported in osteoblastic, osteolytic or mixed lesions, indicating that sclerotic lesions may be less FDG-avid [33]. The additional morphologic information of PET/CT compared with PET alone is certainly of great value in increasing diagnostic sensitivity. Also, significant improvement in diagnostic accuracy has been reported when 18F-fluoride is used for PET or PET-CT for the assessment of malignant skeletal disease. 18F-fluoride is a tracer that, similar to 99mTC-diphosphonate, specifically adsorbs onto bony surfaces with a predilection for sites of active bone formation [30].
An important indication in bone imaging is lesion monitoring after chemotherapy or radiation therapy. It has to be taken into account that on MRI necrotic bone metastases may remain virtually unchanged in morphology or signal characteristics, which may make evaluation of therapy response difficult. Compared with viable tumors, the contrast enhancement is frequently less pronounced and slower in tumors that have responded to a particular therapy. Reduction in tumor size may be delayed and is not a sensitive sign in the assessment of response. Tumor metabolism, and consequently FDG uptake, is highly susceptible to chemotherapy. On the CT image, osteolytic metastases often demonstrate typical sclerotic transformation. In this setting, future studies are needed to evaluate the sensitivity of FDG-PET-CT in assessing the response to chemotherapy and whether sensitivity is reduced in the first days after initiation of therapy. After radiation therapy MRI is particularly helpful, because irradiated lesions are easily distinguishable from new lesions because of the high signal of normal bone marrow on T1-weighted SE images, which is due to conversion of hematopoietic into fatty bone marrow.
Multiple myeloma
Multiple myeloma is a frequent neoplastic disease affecting the bone marrow. It is characterized by expansive growth of malignant plasma cell clones with consecutive destruction of the bony architecture. Predilection sites are the axial skeleton (spine and pelvis), but also the ribs, the shoulder region, skull, and proximal femurs, stressing the need for total body imaging for adequate assessment of the extent of disease. The bone marrow may either be diffusely infiltrated or there may be focal accumulations of atypical plasma cells (Fig. 3).
Fig. 3A 70-year-old man with multiple myeloma. a The radiograph of the pelvis is inconspicuous. b Coronal MS-CT reconstruction of the pelvis in a bone window setting reveals a large area of destruction within the left iliac bone (arrow). c) STIR-WB-MRI confirms focal tumor manifestation within the iliac bone (arrow) and reveals multiple small nodular infiltrations within the sacral bone and pelvis. d MS-CT of the spine shows a compression fracture of Th9. e, f T1-weighted SE- and STIR imaging of the spine reveals diffuse myeloma infiltration of the spine. g Coronal STIR sequences of the pelvis show additional focal infiltration of the left femoral head missed on radiography and MS-CT
In patients with myeloma the basic diagnostic work-up in many institutions includes radiographic examinations of the skull (two planes), the rib cage, the upper arms, the spine (two planes), the pelvis, and the upper legs. This diagnostic approach is still represented in the classic Salmon and Durie staging system of the disease, which includes radiographic, immunohistochemical, and serological factors of the disease, and defines the selection of adequate therapy [34]. However, diagnostic sensitivity of radiography in the detection of myeloma manifestations is rather low and thus allows diagnosis only at advanced stages of the disease when at least 50% of the bone mineral content has been lost [2]. In particular, a diffuse bone marrow infiltration pattern may cause diagnostic problems as it can easily be misdiagnosed as senile osteoporosis. In a study conducted by Baur et al. 55% of focal and 59% of diffuse infiltrations were missed by radiography [35]. With the use of contrast-enhanced sequences and calculation of percentage signal increases the sensitivity of MRI for diffuse myeloma infiltration, especially at earlier stages, can be further increased [36].
Schreiman et al. examined 32 patients with multiple myeloma using single-row CT and radiography [37]. Twelve patients showed osseous affections in both modalities. CT, however, usually demonstrated a more extensive involvement and in 6 out of 13 patients only CT detected myeloma involvement despite normal radiographs. Another study group recently proposed FDG-PET-CT as an alternative to radiographic imaging of the whole body [38]. PET-CT detected more lesions in 16 out of 28 patients (57%) and 9 of these patients had completely negative radiography.
Ghanem et al. compared WB-STIR-MRI using the conventional radiographic skeletal survey in 54 patients with plasma cell neoplasms [16]. Whole-body MRI correctly revealed bone marrow infiltration in 74% of patients, while radiography depicted pathological changes in 55% of patients. Moreover, WB-MRI showed a larger extent of infiltration in 90% of concordant findings.
In two studies, the diagnostic accuracy of MS-CT and MRI was analyzed. Mahnken et al. compared results of four-detector MS-CT and MRI examination of the spine and pelvis in 18 patients with stage III multiple myeloma [39]. A total number of 325 vertebral bodies were evaluated. In MS-CT 231 vertebral bodies were classified as “affected”, compared with only 224 vertebral bodies in MRI. These “false-negative” findings might have been a consequence of response to previous treatment. However, no information about previous therapy was provided in this study. On the other hand, MRI showed 5 affected vertebrae that were considered normal on MS-CT. The false-negatives on MS-CT might be due to early bone marrow infiltration without signs of osseous destruction. Furthermore, the surprisingly high sensitivity of MS-CT in this study may also be caused by pre-selection of a patient group with advanced disease.
In our own study, 30 patients with multiple myeloma were examined with a 1.5-Tesla multi-channel WB-MRI scanner and a 16- and 64-detector MS-CT scanner [17]. MRI showed superior diagnostic accuracy to MS-CT. In particular, the diagnostic sensitivity of MS-CT was inferior to that of WB-MRI (Fig. 3). The high amount of false-negatives on MS-CT may be explained by the fact that early stages of the disease can be visualized on MRI, displaying bone marrow replacement before any destruction of trabecular and cortical bone occurs. False-positive results on MS-CT, on the other hand, may be due to misinterpretation of inhomogeneous osteoporosis as diffuse myeloma infiltration.
Baur et al. were able to show that an extended staging system, including MRI of the spine, has a significant influence on the assessment of prognosis. Using the classic staging system of Durie and Salmon without MRI, 25 out of 77 patients would have been understaged, thus underlining the importance of incorporating the MRI bone marrow status into staging and therapy planning of this disease [40].
Muscle disease
Diagnostic imaging of muscle disease (e.g., polymyositis or muscle dystrophy) represents a challenge as it requires high-resolution whole-body coverage of soft tissue structures to adequately assess the pattern, distribution, and extent of the disease. CT, scintigraphy, and ultrasound are not suitable for this purpose as all these modalities lack sufficient soft tissue contrast, spatial resolution or large FOV imaging options. Other diagnostic tests frequently used, like electromyography, are unspecific and muscle biopsies used as the gold standard have been reported to be false-negative in 10–25% of cases due to sampling errors [41]. MRI, with its precise delineation of fat, muscle, and bone is an ideal candidate for imaging of systemic muscle disease. Moreover, substantial dose exposure in a predominantly younger patient cohort commonly affected by muscle diseases can be avoided. Previously, MRI has been used for a targeted assessment of muscle disease [41, 42]. A combination of T1-weighted SE and T2-weighted pulse sequences with fat saturation, such as STIR, are indispensable for assessing increased fat and water content within the muscle tissue respectively (Fig. 4). Contrast enhancement with Gadolinium chelates also adds to diagnostic accuracy, especially when combined with fat suppression. Since various muscle groups and body parts may be involved in an unpredictable distribution, coverage of the whole body is important.
Fig. 4a Whole-body MRI of a 60-year-old man suffering from severe progressive muscle dystrophy, symmetrically affecting the muscles of the rib cage, abdomen, pelvis, and lower extremities. b WB-STIR shows signs of diffuse reactive edematous processes in the left upper thighs and muscles of the distal lower limbs. c, d T1-weighted imaging displays fatty tissue replacement affecting most of the muscles of the pelvis. Residual adductor muscle tissue is shown with high contrast due to its hypointense signal. e Progressive muscle dystrophy has also occurred in the lower extremities, affecting all compartments
O’Connell et al. previously described WB-STIR imaging for the diagnosis of patients suffering from polymyositis [18]. With the use of parallel imaging techniques WB-STIR imaging can be performed in under 13 min at an inplane resolution of 1.3 × 1.1 mm. With this method, symmetry of muscle involvement and the extent and severity of inflammation can be analyzed, so that an adequate target for biopsy can be identified. During therapy, WB-MRI is particularly helpful in monitoring the disease outcome by visualizing the muscle-to-fat tissue relation or to verify a decrease in inflammation. Also, various drugs, such as steroids, may have side effects that involve the muscles and result in various types of myopathy. Lenk et al. proposed coronal and axial WB-STIR imaging in combination with coronal T1-weighted SE imaging and sagittal T1-/T2-weighted imaging of the spine, as a sensible protocol for systemic muscle disease, resulting in an approximate total scan time of 45 min [19].
However, assessment of distal parts of the upper extremity may be limited. This is due to positioning of the arms on the pelvis and thighs. If the muscles of the forearm are in the focus of interest, additional examination with dedicated coil systems may be required.
Patients with muscular dystrophy, an X-chromosome recessive disease, suffer from progressive destruction of muscle tissue with subsequent replacement by fatty and fibrous tissue. In addition to the morphological information concerning the distribution and extent of replacement of muscle by fatty tissue as provided by WB-MRI, exact quantification of the muscle-to-fat relation is of substantial diagnostic and prognostic importance. In particular, T1-weighted axial WB-MRI in combination with CAD (computer aided diagnostics) applications may be useful for the quantification of total body fat distribution. Interesting results have been reported by Brennan et al. who introduced a fast, automated approach to body fat measurement in healthy individuals as a useful alternative to the body mass index [43].
Future applications
Eustace et al. have proposed WB-MRI for trauma assessment in patients referred for suspected child abuse [44]. For a rapid assessment of acute trauma, especially when multiple organs are affected, MS-CT provides fast and detailed systemic information on potentially life-threatening organ, vessel or bone injury and is the imaging technique of choice. Recently, an accelerated triage MS-CT protocol has been proposed by Koerner et al. for time-effective handling of mass casualty incidents using MS-CT. For a scenario of 15 multiple trauma patients admitted over a period of 2 h within a mass casualty incident a mean total time in the scanner room of 8.9 min was calculated, including patient preparation and image reconstruction [45].
Finally, there may be potential for WB-MRI in the secondary screening of congenital skeletal diseases predisposing to malignancies, like multiple cartilaginous exostoses or histiocytosis X (Fig. 5). However, only case reports have been published on the potential benefits or therapeutic impact in these specific patient groups.
Fig. 5A 35-year-old man with multiple cartilaginous exostoses. a, b Whole-body MRI shows typical manifestations in the metaphyseal parts of the long bones of the upper and lower extremities. c Enlargement of the left knee joint shows an exostosis at the medial side of the femur and at the proximal tibia. d Deformation of the radius. e Exostoses and deformation of both femoral necks. In summary, no indications of malignant transformation (e.g., widening of the cartilaginous cap) were found in this patient
Conclusion
Whole-body imaging is increasingly successfully applied in musculoskeletal imaging, especially in the field of systemic malignant diseases affecting the bone and in diseases predisposing to malignant transformation. Whole-body MRI is able to depict bone marrow pathologies with high resolution and excellent soft tissue contrast by demonstrating signal alterations due to changes in its fat, water, and hematopoietic cell components with high resolution and excellent soft tissue contrast. Together with CT or PET-CT and its valuable additional metabolic information, it has great potential in the more comprehensive, more accurate, and earlier diagnosis of musculoskeletal diseases. Although further evaluation of the true potential of whole-body applications is awaited, they are promising tools aiding the more efficient management of patients suffering from systemic malignant or benign diseases of the soft tissue and bone.

whole-body
imaging
musculoskeletal
magnetic resonance imaging