Clin Orthop Relat Res (2017) 475:498–507 DOI 10.1007/s11999-016-5118-3 Clinical Orthopaedics and Related Research® A Publication of The Association of Bone and Joint Surgeons® CLINICAL RESEARCH What Factors are Associated With Quality Of Life, Pain Interference, Anxiety, and Depression in Patients With Metastatic Bone Disease? Q. M. J. van der Vliet BSc, N. R. Paulino Pereira MD , S. J. Janssen MD, F. J. Hornicek MD, MS, PhD, M. L. Ferrone MD, J. A. M. Bramer MD, PhD, C. N. van Dijk MD, PhD, J. H. Schwab MD, MS Received: 22 June 2016 / Accepted: 4 October 2016 / Published online: 17 October 2016 Ó The Association of Bone and Joint Surgeons1 2016 Abstract Background It would be helpful for the decision-making process of patients with metastatic bone disease to understand which patients are at risk for worse quality of life (QOL), pain, anxiety, and depression. Normative data, and where these stand compared with general population scores, can be useful to compare and interpret results of similar patients or patient groups, but to our knowledge, there are no such robust data. One of the authors certifies that he (SJJ), or a member of his or her immediate family, has or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from the Anna Foundation (Oegstgeest, The Netherlands), an amount of less than USD 10,000 from the De Drie Lichten Foundation (Hilversum, The Netherlands), an amount of less than USD 10,000 from the KWF Kankerbestrijding (Amsterdam, The Netherlands), and an amount of less than USD 10,000 from the Michael van Vloten Foundation (Rotterdam, The Netherlands). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research1 editors and board members are on file with the publication and can be viewed on request. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This study was performed at Massachusetts General Hospital & Brigham and Women’s Hospital, Boston, MA, USA. Electronic supplementary material The online version of this article (doi:10.1007/s11999-016-5118-3) contains supplementary material, which is available to authorized users. Q. M. J. van der Vliet, N. R. Paulino Pereira, S. J. Janssen, F. J. Hornicek, J. H. Schwab Department of Orthopaedic Surgery, Orthopaedic Oncology Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 123 Questions/Purposes We wished (1) to assess what factors are independently associated with QOL, pain interference, anxiety, and depression in patients with metastatic bone disease, and (2) to compare these outcomes with general US population values. Methods Between November 2011 and February 2015, 859 patients with metastatic bone disease presented to our orthopaedic oncology clinic; 202 (24%) were included as they completed the EuroQOL-5 Dimension (EQ-5DTM), PROMIS1 Pain Interference, PROMIS1 Anxiety, and PROMIS1 Depression questionnaires as part of a quality improvement program. We did not record reasons for not responding and found no differences between survey respondents and nonrespondents in terms of age (63 versus 64 years; p = 0.916), gender (51% men versus 47% men; p = 0.228), and race (91% white versus 88% white; p = 0.306), but survey responders were more likely to be married or living with a partner (72%, versus 62%; p = 0.001). We assessed risk factors for QOL, pain interference, anxiety, and depression using multivariable linear regression analysis. We used the one-sample signed rank test to assess whether scores differed from US population averages drawn from earlier large epidemiologic studies. M. L. Ferrone Department of Orthopaedic Surgery, Orthopaedic Oncology Service, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA J. A. M. Bramer, C. N. van Dijk Department of Orthopaedic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands N. R. Paulino Pereira (&) Massachusetts General Hospital, Room 3.946, Yawkey Building, 55 Fruit Street, Boston, MA 02114, USA e-mail: nunorui.pp@gmail.com Volume 475, Number 2, February 2017 Results Younger age (b regression coefficient [b],\0.01; 95% CI, 0.00–0.01; p = 0.041), smoking (b, 0.12; 95% CI, 0.22 to 0.01; p = 0.026), pathologic fracture (b, 0.10; 95% CI, 0.18 to 0.02; p = 0.012), and being unemployed (b, 0.09; 95% CI, 0.17 to 0.02; p = 0.017) were associated with worse QOL. Current smoking status was associated with more pain interference (b, 6.0; 95% CI, 1.6–11; p = 0.008). Poor-prognosis cancers (b, 3.8; 95% CI, 0.37–7.2; p = 0.030), and pathologic fracture (b, 6.3; 95% CI, 2.5–7.2; p = 0.001) were associated with more anxiety. Being single (b, 5.9; 95% CI, 0.83–11; p = 0.023), and pathologic fracture (b, 4.4; 95% CI, 0.8–8.0; p = 0.017) were associated with depression. QOL scores (0.68 versus 0.85; p \ 0.001), pain interference scores (65 versus 50; p\0.001), and anxiety scores (53 versus 50; p = 0.011) were worse for patients with bone metastases compared with general US population values, whereas depression scores were comparable (48 versus 50; p = 0.171). Conclusions Impending pathologic fractures should be treated promptly to prevent deterioration in QOL, anxiety, and depression. Our normative data can be used to compare and interpret results of similar patients or patient groups. Future studies could focus on specific cancers metastasizing to the bone, to further understand which patients are at risk for worse patient-reported outcomes. Level of evidence Level III, prognostic study. Introduction The main goal when treating patients with metastatic bone disease is to preserve or even improve quality of life (QOL) [7, 29]. Questionnaires that measure QOL can quantify treatment effectiveness and guide clinical decision-making [7, 18, 30]. Several studies identified risk factors for QOL in patients with metastatic bone disease; [8, 25, 28, 29] however, these often were measured after specific treatment(s), and therefore do not represent QOL for all patients with metastatic bone disease. It would be useful to more fully understand which patients are at risk for worse QOL, pain, anxiety, and depression, so that deterioration for these patients can be anticipated and potentially overcome with medical treatment. In addition, it is helpful to have normative data for patients with metastatic bone disease to be able to compare and interpret results of similar patients or patient groups. To our knowledge, there are no rigorous sources to date that provide such information. Therefore, we sought to identify factors independently associated with QOL, pain interference, anxiety, and Quality of Life in Metastatic Bone Disease 499 depression. Secondly, we compared these patient-reported outcome scores with general US population scores. Patients and Methods Study Design, Setting, and Subjects After approval by the institutional review board of Massachusetts General Hospital, we analyzed prospectively gathered patient-reported outcome data of patients with bone metastases from solid tumors, myeloma, or lymphoma, who presented to our clinic between November 1, 2011 and February 1, 2015. As part of a quality improvement program, patients completed the following questionnaires before visiting the surgeon at our orthopaedic oncology service since November 2011: the EuroQOL 5 Dimension Questionnaire (EQ-5DTM), PatientReported Outcomes Measurement Information System (PROMIS1) Pain Interference, PROMIS1 Anxiety, and PROMIS1 Depression. Through the information system (Research Patient Data Registry) from Massachusetts General Hospital, we identified 16,769 unique patients who received the ICD-9 code for ‘‘Secondary malignant neoplasm of bone and bone marrow’’ between February 1990 and February 2015; 1714 of those patients were seen at our orthopaedic oncology clinic, of whom 859 were seen during the period of the quality improvement program (November 2011 to February 2015). Of the 859 potentially eligible patients, 202 (24%) completed the survey and 657 (76%) did not (Fig. 1). We were unable to track reasons for nonparticipation, but we did analyze differences in baseline characteristics between the surveyed and nonsurveyed patients. There were no differences in age (63 versus 64 years; p = 0.916), sex (51% men versus 47% men; p = 0.228), and race (91% white versus 88% white; p = 0.306), but survey responders were more likely to be married or living with a partner (72% versus 62%; p = 0.001) (Appendix 1. Supplemental material is available with the online version of CORR1). We therefore believe that our results can be generalized to the overall population of patients with bone metastasis presenting to an orthopaedic oncology clinic. Questionnaires were completed through the REDCap (Research Electronic Data Capture) data capture tool on a tablet computer [14]. We included the first completed survey in the case patients had completed surveys multiple times, as not to violate the statistical assumption of independence. 123 500 van der Vliet et al. Clinical Orthopaedics and Related Research1 Fig. 1 This flow chart shows the selection procedure of the included cohort. The ICD-9 code 198.5 corresponds to ‘‘Secondary malignant neoplasm of bone and bone marrow’’ Outcome Measures and Explanatory Variables Our outcome measures were (1) QOL, as measured with the EQ-5DTM questionnaire (completed by all patients), (2) how pain interfered with physical function as measured with the PROMIS1 Pain Interference questionnaire (completed by 143; 71%), (3) anxiety as measured with the PROMIS1 Anxiety questionnaire (completed by 138; 68%), and (4) depression as measured with the PROMIS1 Depression questionnaire (completed by 136; 67%). The latter three questionnaires were not completed by all 123 patients as these were introduced to the quality improvement program at a later time (August 1, 2012). We assessed baseline differences between patients who did not complete a PROMIS1 questionnaire (n = 56), and those who did (n = 146). There were no differences in median age (62 versus 64 years; p = 0.972), sex (46% male versus 53% male; p = 0.432), marital status (73% married versus 72% married; p = 0.271), median Charlson Comorbidity Index (6 versus 6; p = 0.806), pathologic fracture (27% versus 29%; p = 0.862), or previous surgery (14% versus 8.9%; p = 0.304). Volume 475, Number 2, February 2017 The EQ-5DTM-3L questionnaire covers five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and each dimension is divided into three levels (no problems, moderate problems, or extreme problems). The EQ-5DTM describes 245 unique health states [24]. Fryback et al. [10] obtained age-by-gender EQ5DTM norms for adults in the US; we compared the EQ5DTM scores to the value of 0.85, based on the age of our study participants. The PROMIS1 was established by the National Institutes of Health (NIH) to develop standardized item banks to assess physical, mental, and social well-being in the medical field. The PROMIS1 Pain Interference item bank (six items) assesses the extent to which pain interferes with functioning. The PROMIS1 Anxiety questionnaire (six items) includes questions regarding fear, anxious misery, hyperarousal, and somatic symptoms related to arousal. The PROMIS1 Depression questionnaire (six items) focuses on negative mood, decrease in positive affect, information-processing deficits, negative views of self, and negative social cognition. All PROMIS1 scores have a general US population-based mean T-score of 50; these scores are not adjusted by age or gender [5]. Two researchers (QvdV, SJJ) extracted the following explanatory variables from medical records in a retrospective manner, as these were known or suggested to be associated with patient-reported outcomes [8, 25, 28, 29]: age, sex, race, employment status, marital status, smoking status, comorbidity status, BMI in kg/m2, primary tumor type, time between diagnosis of primary tumor and survey, time between diagnosis of metastatic disease and survey, location of the bone metastasis leading to the consultation (spine, lower extremity, upper extremity, pelvis, multiple, and other locations), current radiotherapy, current systemic therapy, prior surgery for bone metastasis, pathologic fracture (an impending pathologic fracture was not considered a fracture), presence of other bone metastases, and presence of visceral or brain metastases. We assessed the comorbidity status using a modified Charlson Comorbidity Index; this is an index weighting 12 comorbidities known to be associated with 10-year survival [6]. We used a modified Charlson Comorbidity Index calculated by a previously described algorithm based on ICD9 codes [23]. The presence of additional comorbidities was based on the modified Charlson Comorbidity Index and defined as the presence of conditions other than metastatic bone disease, multiple myeloma, or lymphoma. We extracted BMI closest to completion of the survey and omitted values recorded longer than 90 days before the survey. ‘‘Former smoker’’ was defined as stopped smoking at least 1 year before the survey. Based on a study by Katagiri et al. [17], we categorized primary tumors as those with a relatively good prognosis (breast, kidney, prostate, Quality of Life in Metastatic Bone Disease 501 thyroid, myeloma, and lymphoma), and those with a relatively poor prognosis (all other tumor types). Systemic therapy was defined as any type of hormonal therapy, chemotherapy, or immunotherapy for the primary cancer. The fracture status, presence of other bone metastases, and visceral metastases were derived from radiology reports. An independent researcher (NRPP) crosschecked a random 10% sample of the retrospectively collected data to ensure a robust database; there were less than 5% inconsistencies overall, and there were no repeated inconsistencies within one variable. Statistical Analysis Continuous variables were presented as medians with interquartile ranges (IQR), and categorical variables as frequencies with percentages. Data were analyzed using nonparametric tests, as histograms suggested nonnormal distribution of continuous variables. We did an exploratory bivariate analysis to assess differences in outcome measures using the Mann-Whitney U test for dichotomous explanatory variables, Kruskal-Wallis test for categorical explanatory variables, and Spearman’s rank correlation coefficient for continuous explanatory variables. We used stepwise backward multivariable linear regression analysis—retaining variables with a p value less than 0.10—to assess if explanatory variables (as identified by the bivariate analyses) were independently associated with the outcome measures. We used the one-sample signed rank test to assess whether scores differed from general US population averages. All statistical analyses were performed with STATA1 13.0 (StataCorp LP, College Station, TX, USA), and twotailed p values less than 0.05 were considered significant. Patient Demographics The study population consisted of 104 (51%) men and 98 (49%) women, with a median age of 63 years (range, 27– 89 years) (Table 1). Lung cancer was the most common primary cancer (35; 17%), followed by breast cancer (33; 16%), and multiple myeloma (33; 16%). The most common location for a bone lesion was the spine (72; 36%), and 57 (28%) patients presented with a pathologic fracture. Twenty-one (10%) patients had undergone prior surgery for their metastatic bone lesion(s), with a median of 132 days (IQR, 23–520 days; range, 2–1617 days) between the surgery and survey completion. Seventy-nine (39%) were being treated with systemic therapy, and nine (4%) were receiving radiotherapy for their bone lesion(s) at the time of completing the survey. 123 502 Clinical Orthopaedics and Related Research1 van der Vliet et al. Table 1. Baseline characteristics of 202 patients Characteristic Median Interquartile range Age (years) 63 54–72 Modified Charlson Comorbidity Index* 6.0 6.0–8.0 BMI (kg/m2)* 27 24–31 Time between diagnosis of primary tumor and survey (months)* 26 4.1–78 Time between diagnosis of metastatic disease and survey (months)* 7.4 0.4–34 Number % Men 104 51 White race* 174 91 Additional comorbidities* 94 47 79 118 40 60 Married/living with partner 144 72 Separated/divorced/widowed 35 18 Single 21 11 Employment status* Employed Unemployed Marital status* Smoking status* Never smoked 79 41 Former smokerà 81 42 Current smoker 35 18 Lung 35 17 Breast 33 16 Multiple myeloma 33 16 Kidney 28 14 Prostate 13 6 60 30 Spine 72 36 Lower extremity 40 20 Upper extremity 31 15 Pelvis 27 13 Multiple 30 15 Other|| 2 1 9 4 Primary tumor type Other/unknown§ Location of presenting metastasis Current radiotherapy Current systemic therapy 79 39 Prior surgery for bone metastasis 21 10 Pathologic fracture 57 28 Multiple bone metastases 127 63 Lung/liver/adrenal/brain metastases 81 40 *Modified Charlson Comorbidity Index was available for 200 patients (99%), BMI was available for 198 patients (98%), race was available for 191 patients (95%), additional comorbidities were available for 200 patients (99%), employment status was available for 197 patients (98%), marital status was available for 200 patients (99%), smoking status was available for 195 patients (97%), time between diagnosis of primary tumor and survey was available for 193 patients (96%), and time between diagnosis of metastatic disease and survey was available for 196 patients (97%); based on any additional comorbidity in addition to the metastatic disease score following the Charlson Comorbidity Index; àquit at least 1 year before survey; §thyroid (n = 8), lymphoma (n = 6), colorectal (n = 6), adenocarcinoma (n = 6), neuroendocrine (n = 5), esophageal (n = 4), melanoma (n = 3), liver (n = 3), bladder (n = 2), endometrial (n = 2), ovarian (n = 1), and pancreatic (n = 1); ||rib (n =1), occipital condyle (n = 1). 123 Volume 475, Number 2, February 2017 Quality of Life in Metastatic Bone Disease 503 Table 2. Multivariable linear regression analysis assessing factors independently associated with patient-reported outcomes Explanatory variables per questionnaire b regression coefficient (95% CI) Standard error p Value \ 0.01 (0.00–0.01) 0.001 0.041} EQ-5DTM index Age (in years) Smoking status* Never smoked Reference Former smoker 0.05 ( 0.13 to 0.03) 0.04 0.252 Current smoker 0.12 ( 0.22 to 0.01) 0.05 0.026} 0.10 ( 0.18 to 0.02) 0.04 0.012} Reference 0.09 ( 0.17 to 0.02) 0.04 0.017} Pathologic fracture No Reference Yes Employment status* Employed Unemployed PROMIS 1 Pain Interference Smoking status* Never smoked Reference Former smoker 3.1 ( 0.37 to 6.7) 1.72 0.080 Current smoker 6.0 (1.6–11) 2.25 0.008} 1.73 0.030} PROMIS 1 Anxiety Primary tumor typeà Good prognosis Reference Poor prognosis 3.8 (0.37–7.2) Pathologic fracture No Reference Yes 6.3 (2.5–7.2) 1.90 0.001} Married/living with partner Separated/divorced/widowed Reference 0.53 ( 4.0 to 5.0) 2.27 0.817 Single 5.9 (0.83–11) 2.54 0.023} 1.82 0.017} PROMIS1 Depression Marital status* Pathologic fracture No Reference Yes 4.4 (0.8–8.0) Two-tailed p value less than 0.05; adjusted R squared values for the multivariate analyses were 0.0586 for the EQ-5DTM, 0.0407 for the PROMIS1 Pain Interference, 0.0902 for the PROMIS1 Anxiety, and 0.0632 for the PROMIS1 Depression; *marital status was available for 200 patients (99%); quit at least one year before survey; àprimary tumor type with good prognosis includes breast, kidney, prostate, thyroid, myeloma and lymphoma, and with poor prognosis includes all other tumor types; EQ-5DTM = EuroQol 5 Dimension Questionnaire; PROMIS1 = Patient-Reported Outcomes Measurement Information System. } Results Factors Associated With More Pain Interference Factors Associated With Worse QOL Current smoking status was the only factor associated with worse pain interference scores (b, 6.0; 95% CI, 1.6–11; p = 0.008) (Table 2). After controlling for relevant confounding variables, we found that younger age (b regression coefficient [b], \ 0.01; 95% CI, 0.00–0.01; p = 0.041), current smoking status (b, 0.12; 95% CI, 0.22 to 0.01; p = 0.026), pathologic fracture (b, 0.10; 95% CI, 0.18 to 0.02; p = 0.012), and being unemployed (b, 0.09; 95% CI, 0.17 to 0.02; p = 0.017) were independently associated with worse QOL (Table 2). Factors Associated With More Anxiety After controlling for relevant confounding variables, we found that a primary tumor type with poor prognosis (b, 3.8; 95% CI, 0.37–7.2; p = 0.030), and pathologic fracture 123 504 Clinical Orthopaedics and Related Research1 van der Vliet et al. Table 3. Patient-reported outcomes for patients with bone metastases, and comparison with general population values Questionnaire Number (%) Median (interquartile range) EQ-5DTM index 202 (100) 0.68 (0.40–0.81) ‘ PROMIS1 Pain Interference 143 (71) 65 (56–70) 50 \ 0.001* PROMIS1 Anxiety 138 (68) 53 (39–61) 50 0.011* 136 (67) 48 (38–57) 50 0.171 PROMIS 1 Depression *Significant; EQ-5D TM = EuroQol 5 Dimension Questionnaire; PROMIS (b, 6.3; 95% CI, 2.5–7.2; p = 0.001) were independently associated with worse anxiety scores (Table 2). Factors Associated With Depression After controlling for relevant confounding variables, we found that pathologic fracture (b, 4.4; 95% CI, 0.8–8.0; p = 0.017), and being single (b, 5.9; 95% CI, 0.8–11; p = 0.023) were independently associated with worse depression scores (Table 2). Comparison With General US Population Norms Patients with metastatic bone disease had worse QOL scores than the US population norm of 0.85 (0.68; range, 0.04 to 1; p\0.001), worse PROMIS1 Pain Interference scores than the US population norm of 50 (T-score, 65; range, 41–76; p \ 0.001), and worse PROMIS1 Anxiety scores than the US population norm of 50 (T-score, 53; range, 39–79; p = 0.011). Patients with metastatic bone disease had PROMIS1 Depression scores comparable to the US population norm of 50 (T-score, 48; range, 38–73; p = 0.171) (Table 3). Discussion QOL plays a crucial role in the treatment of metastatic bone disease [7, 29], and questionnaires that measure QOL can quantify treatment effectiveness and guide clinical decision-making [7, 18, 30]. Previous studies identified risk factors for QOL after medical treatments [8, 25, 28, 29], although it would be useful for clinical decision-making to understand which patients are more prone to have worse QOL regardless of any (prior) treatment. Furthermore, it would be helpful to have normative data for these patients to be able to compare and interpret results of similar patients or patient groups. We found that having a pathologic fracture was independently associated with worse QOL, increased anxiety, and more depression. In addition, 123 1 General population value 0.85 p Value \ 0.001* = Patient-Reported Outcomes Measurement Information System. younger age, current smoking status, and being unemployed were independently associated with worse QOL. Current smoking status was independently associated with more pain interference. A primary tumor type with poor prognosis was associated with more anxiety, and being single was associated with more depression. Patients with metastatic bone disease reported worse QOL, more pain interference, and more anxiety compared with general population values; their depression scores were not different with the numbers available. This study has limitations. First, selection bias might have occurred, as we had patient-reported outcomes on only 24% [202/859] of the eligible patients who presented to our clinic. Nonresponders more often were single, and being single was associated with worse depression scores; if all 859 eligible patients had been included, this could have worsened overall patient-reported outcome scores (especially depression scores), giving larger differences between our sample and US population norms. Second, 56 (28%) of the 202 patients did not complete a PROMIS1 questionnaire, resulting in reduced statistical power for PROMIS1- related outcomes. However, we found no baseline differences between the patients who did and did not complete the PROMIS1 questionnaires. Third, questionnaires were completed at different stages of treatment. This cross-sectional survey study represents the breadth of patients with bone metastasis who present to an orthopaedic oncology clinic; some patients filled out the questionnaires during their preoperative visit, whereas others completed the survey after an extensive surgical procedure. The normative data for patient-reported outcomes that we present are not reflections of the effectiveness of certain medical treatments that we provide, and should not be interpreted as such. Fourth, two researchers collected several variables in a retrospective manner (except for the patient-reported outcomes); these variables might have information bias. Another researcher verified a random 10% sample (21 patients) of the database to detect inconsistencies in all retrospectively collected data; less than 5% of the data were discrepant, and discrepancies were not consistent within one variable. Therefore we considered this a minor limitation. Fifth, we Volume 475, Number 2, February 2017 included predominantly white patients from an orthopaedic clinic at a tertiary care hospital in an urban area, therefore our results may not be generalizable to all patients with metastatic bone disease or patients being treated in other settings. Patients who present to our clinic often have an acute or impending fracture or a painful bone lesion; this might result in a sicker patient population compared with patients who do not consult an orthopaedic surgeon [1]. Therefore, our results might show a slight underestimation of QOL for patients with bone metastases. Sixth, we used ICD-9 codes to identify eligible patients and to extract the modified Charlson Comorbidity Index. Coding might have been inaccurate, although we believe this is limited and not of influence on our results. Seventh, outcome measures and explanatory variables were not available for all patients. However, missing data were relatively low (PROMIS1 Pain Interference missing in 29%; PROMIS1 Anxiety missing in 32%; PROMIS1 Depression missing in 33%; range of percentages of missing data for explanatory variables 1% to 4%). Eighth, the Karnofsky Performance Score was found to be associated with QOL in previous studies [8, 28, 29]. Unfortunately, data on this score were available only for a very small number of patients in our cohort, therefore we could not assess the effect of the performance score on patient-reported outcomes. Ninth, one may advocate that it is inappropriate to include patients with hematologic cancers in this study because these cancers (often) have a better prognosis, which might modify the patients’ perception of the disease. We tried to account for this by including the variable ‘‘primary tumor type’’, where hematologic malignancies accounted for 32% (39/ 121) of the ‘‘good prognosis’’ group. Finally, the normative data on PROMIS1 scores we used are not adjusted by age or gender [5]. As we observed in our data, QOL scores may vary based on age: likely, this is also the case in the general population [15, 16, 19]. This limitation might have resulted in an unfair comparison with general population values for PROMIS1 questionnaire outcomes. Future studies will need to perform such adjustments, as it seems nearly certain that age and gender would influence patients’ PROMIS1 scores. To our knowledge, our findings that patients who were younger, patients who were smokers, patients who were not employed, and patients with pathologic fractures all had poorer QOL, are novel. However, other studies have reported on other risk factors. Choi et al. [8] measured QOL by giving the EQ-5DTM questionnaire to 922 patients after surgery for metastatic spine disease; predictive factors for postoperative QOL were the preoperative EQ-5DTM score, the Frankel score, and the Karnofsky performance status. Westhoff et al. [28] collected QOL for 956 patients with breast, prostate, and lung cancers after irradiation for painful bone metastases by giving the Rotterdam Symptom Quality of Life in Metastatic Bone Disease 505 Checklist, and found that patients with lung cancer had worse QOL scores than patients with prostate and breast cancers. In a study by Wong et al. [29], 396 patients with metastatic bone disease completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases module: a Karnofsky Performance scale greater than 80 (compared with less than 80) and breast or prostate cancer (compared with other cancer types) were associated with better QOL. Rustøen et al. [25] obtained QOL information from 157 oncology outpatients with pain from bone metastasis, using the Multidimensional Quality of Life Scale-Cancer. Depression, social functioning, and physical functioning were the factors associated with QOL. Having a pathologic fracture was independently associated with worse QOL, more anxiety, and depression. We believe that patients with a pathologic fracture have worse QOL owing to increased pain and disability (as these are components of the EQ-5DTM) [24], and more anxiety and depression owing to overall deterioration in health and accompanying death anxiety. This stresses that it is of utmost importance to prevent pathologic fractures, and could serve as a basis for a lower threshold for surgery (such as intramedullary nailing) in patients with impending fractures from metastatic bone lesions. Patients who were unemployed reported worse QOL, but it is unclear if poor QOL led to unemployment or vice versa. Wong et al. [29] studied 396 patients with bone metastases from various cultures and found that employment status was not associated with QOL. This mixture of cultures might have led to a different contribution of employment status, showing that the extrapolarity of our results to other countries is limited. Current smoking status was associated with worse QOL and more pain interference in our study patients. Although the psychological and physiologic reasons remain unclear, pain and tobacco addiction are theorized to interact in a bidirectional manner [22]; individuals with pain are more likely to be dependent on tobacco, and tobacco addiction is a risk factor for having chronic pain develop. Although the direction of causality is unclear, this interaction gives a positive feedback loop between tobacco abuse and pain, leading to worsening of both conditions [9]. Patients with relatively poor-prognosis tumor types reported more anxiety compared with patients with goodprognosis primary tumor types; this might be attributable to the awareness of a poorer prognosis and fear of death. We broke down this variable further per cancer type and ascertained that patients with lung cancer and adenocarcinoma reported more anxiety compared with patients with breast cancer, multiple myeloma, renal cancer, prostate cancer, or thyroid cancer (Table 4). We also stratified for pathologic fracture, as this also was a risk factor; these 123 506 Clinical Orthopaedics and Related Research1 van der Vliet et al. Table 4. PROMIS1 Anxiety t-scores with 95% CIs, stratified for most common primary tumor types, and pathologic fracture Patient group Poor-prognosis tumors* Lung carcinoma n = 26 All patients (n = 54 (49–61) 138) Good-prognosis tumors* Adenocarcinoma Breast carcinoma n=5 n = 23 Multiple myeloma n = 22 Renal cell carcinoma n = 19 Prostate carcinoma n=9 Thyroid carcinoma n=5 All patients n = 138 57 (54–63) 53 (46–63) 51 (39–62) 51 (39–63) 49 (39–51) 49 (39–51) 53 (39– 61) Pathologic fracture No (n = 100) 51 (39–57) 56 (52–30) 51 (39–61) 54 (39–63) 46 (39–57) 49 (43–53) 49 (39–51) 51 (39– 57) Yes (n = 38) 61 (53–63) 74 (74–74) 57 (51–63) 50 (46–58) 66 (63–69) 39 (39–39) – 58 (49– 63) The most common primary tumor types are included (n[5); *based on study by Katagiri et al. [17], primary tumors were categorized as tumors with a relatively good prognosis (breast, kidney, prostate, thyroid, myeloma, and lymphoma), and tumors with a relatively poor prognosis (all other tumor types). normative data can be used to compare and interpret results of similar patients or patient groups. Furthermore, awareness of anxiety and referral for psychological counseling in patients with poor-prognosis tumor types is recommended. Studies show that in the general population older age is associated with worse QOL scores [15, 16, 19], whereas in our study population younger age was associated with worse QOL. We speculate that younger patients may be more traumatized when receiving a diagnosis of metastatic disease (it comes more unexpectedly), have greater responsibilities to their family and community, and have more life goals compared with older patients [20, 27, 32]. Like in our study, previous studies showed an association between being married and better QOL [3, 11, 29]. Goodwin et al. [13] suggested that married patients with cancer may have a better QOL because they are diagnosed at an earlier stage, they may show better response to treatment, and because they benefit from the social support and care-taking skills of the spouse. To our knowledge, this is the first study comparing QOL, pain interference, anxiety, and depression scores for patients with bone metastases with general population values. Previously, patients with any type of cancer were found to have similar QOL compared with a general US adult population sample [4]. In light of this, we questioned why patients with bone metastases from our cohort reported worse QOL. Patients with bone metastases might have more pain, reduced mobility, impaired role functioning, and reduced physical performance [2]. Pain interference scores were higher compared with US population values; this can be explained by the painful conditions (pathologic fractures, painful bone lesions) that are the most common reasons for presenting to an orthopaedic surgeon [1]. Furthermore, we believe that patients 123 had higher anxiety scores owing to fear of pain or to death anxiety [26]. Death anxiety is common in patients with advanced cancer and has been associated with generalized anxiety [12, 21, 26]. Surprisingly, depression scores were comparable to general population values. Previous studies explained this phenomenon as emotional and spiritual adaptation, and taking the cancer diagnosis in consideration when evaluating health status [21, 31]. Physicians can use the factors we associated with poorer scores for QOL, pain interference, anxiety, and depression to anticipate which patients might need additional psychosocial support during treatment for metastatic bone disease. 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