Impact of Musculoskeletal Disease on Quality of Life in Long-Standing

European Journal of Endocrinology (2008) 158 587–593 ISSN 0804-4643

CLINICAL STUDY Impact of musculoskeletal disease on quality of life in long-standing acromegaly Anne Miller, Helen Doll1, Joel David and John Wass2 Department of Rheumatology, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK, 1Department of Public Health, University of Oxford, Oxford OX3 7LF, UK and 2Department of Endocrinology, OCDEM, The Churchill Hospital, Oxford OX3 7LJ, UK (Correspondence should be addressed to A Miller; Email: [email protected])

Abstract Objective: To provide rheumatological assessment of patients with long-standing acromegaly and investigate the impact of musculoskeletal disease on quality of life. Design: Cross-sectional observational study. Methods: Fifty-eight patients diagnosed with acromegaly at least 5 years previously were interviewed and examined by a rheumatologist. Each patient completed the short form-36 (SF-36), arthritis impact measurement scales 2 (AIMS2) and acromegaly quality of life questionnaires (AcroQol). Results: Fifty-two out of 58 (90%) reported musculoskeletal pain, with 29 (50%) reporting neck pain. Hip osteoarthritis was present in 49 (84%) and knee osteoarthritis in 20 (34%). Half the patients (52%) reported sleep disturbance, but only 2 (3.5%) had fibromyalgia. Ten (17.2%) had previously undergone carpal tunnel decompression. Fifty-one (88%) patients had consulted their general practioner and 31 (54%) complementary therapists. SF-36, AIMS2 and AcroQol scores were lower in patients with musculoskeletal pain. Conclusions: This study of musculoskeletal problems in patients with acromegaly reports systematic rheumatological examination, use of medical services and quality of life scores. Musculoskeletal problems should be routinely addressed in acromegaly by both endocrinologist and rheumatologist and a multidisciplinary approach taken to management.

European Journal of Endocrinology 158 587–593

Introduction correlate with greater joint damage (1, 3, 12). Other factors will contribute to development and severity of A number of studies have documented clinical features acromegalic arthropathy, as in osteoarthritis, including of acromegalic arthropathy (1–7) but little has been age, gender, genetic factors, local biomechanics, injury, published on how this affects physical function and obesity, deformity and muscle weakness (13). quality of life and there are no studies detailing We investigated pain and joint disease in patients systematic rheumatological examination of such with long-standing acromegaly from a rheumatological patients. In a review of 45 case notes and 20 patients perspective. Information was collected on employment, with acromegaly, 22% male and 36% female patients use of medical services, function and quality of life with were moderately to severely disabled by their arthro- a systematic rheumatological examination including pathy (8). A good response to treatment, assessed joints, carpal tunnel compression and fibromyalgia. The clinically and by growth hormone (GH) estimation, was latter was included in view of sleep abnormalities associated with better employment and less severe joint characterizing acromegaly (14). The effect of muscu- disease. Biermasz et al. evaluated both short form 36 loskeletal pain on quality of life was explored using three (SF-36) and acromegaly quality of life (AcroQol) and questionnaires: SF-36 version 2 (15), arthritis impact first reported that patients with joint problems and measurement scales 2 (AIMS2) (16) and AcroQol (17). controlled acromegaly had poorer QoL (9). Various factors would be expected to influence long- standing changes of acromegalic arthropathy, such as cartilage hypertrophy and duration of uncontrolled GH Methodology and insulin-like growth factor 1 (IGF1). Control of IGF1 and GH by somatostatin agonists has been shown to The study was conducted at Department of Endo- reduce joint thickness in acromegaly by ultrasono- crinology at The Churchill Hospital, Oxford and Depart- graphy (10, 11). High levels and long duration of excess ment of Rheumatology at the Nuffield Orthopaedic growth mediators alone have not been shown to Centre, Oxford.

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Study population population (18) and with those of 48 patients with non- functioning pituitary tumours of mean age 59 (S.D. 12) The study population comprised patients under review years from the Oxfordshire region (19). at The Churchill Hospital with acromegaly diagnosed at The AIMS2 is a questionnaire developed to assess least 5 years previously, anticipating they were more health status in subjects with rheumatic disease (16).It likely to have controlled acromegaly and irreversible is generally used in rheumatoid and osteoarthritis and joint changes. All eligible patients actively followed-up its use as a tool in acromegalic arthropathy was at the time that we could contact were invited to explored here. There are 12 scales addressing function participate by letter. Non-responders were sent one and pain: mobility level, walking and bending, hand further letter. All the participants were interviewed and and finger function, arm function, self-care tasks, examined by the same rheumatologist. household tasks, social activity, support from family and friends, arthritis pain, work, level of tension and Data collection mood. It has a potential range of scales from 0 to 10, Demographic data were collected from medical records with the worst possible score of 10. including age at diagnosis, pre-diagnosis disease duration, The AcroQol is a disease-specific questionnaire for treatment, and date of biochemical cure. This was acromegaly containing 22 items scored globally and estimated when a normal age-related IGF1 and normal divided into two scales evaluating physical and GH curve (mean !5 mU/l) were achieved and main- psychological aspects (17). tained until the date of the interview. Duration of uncontrolled acromegaly was calculated by summation Statistical analysis of pre- and post-diagnosis disease durations from diagnosis to date of control, or to time of study interview Data analysis was performed using SPSS for Windows if uncontrolled. Acromegaly was defined as uncontrolled if version 12 (Chicago, Illinois 60606, US). The SF-36, the GH curve and/or IGF1 were not within this normal AIMS2 and AcroQol were scored using standard range or had lapsed from a previously normal report. procedures. Missing values were only replaced with Information on musculoskeletal disease at presen- the mean of other items in the relevant scale if all other tation was obtained from patient recall and medical items were present for the AIMS2 and the AcroQol, and records. Patients were asked about the presence of if more than half were present for the SF-36, following musculoskeletal pain at diagnosis and currently, the standard guidelines. AIMS2 scale scores were symptoms of carpal tunnel syndrome (CTS), subjective modified to adjust for co-morbidity according to the sleep disturbance, use of medical services for muscu- User’s Guide Data. loskeletal problems, referral for medical and surgical Data are presented as N (%) or mean (S.D.) as consultations or allied health professionals, further appropriate. Comparisons between groups were under- investigations and use of complementary therapies. taken using c2 tests for categorical data and t-tests or Clinical examination included body mass index and Mann–Whitney tests for continuous data. Independent number of fibromyalgic tender points. Examination of association of factors with the physical functioning each joint included pain, tenderness, joint swelling, loss domain of the SF-36 was explored with stepwise linear of range of movement and presence of deformity. regression analysis. Statistical significance was taken at Lumbosacral movement was measured using a modified P!0.05 throughout. Schober Index and was defined as limited if !5 cm. Clinical evidence of CTS was sought by inducing paraesthesia in the distribution of the median nerve Results on percussion of the median nerve at the wrist (Tinel’s test) and sustained palmar flexion of the wrist Eighty-six patients were identified from department (Phalen’s test). records as fulfilling the inclusion criteria and 58 (67%) were recruited over 1 year. Figure 1 is a flow chart showing participation and reasons for non-partici- Quality of life assessments pation. Participants and non-participants did not differ Participants were asked to complete the AIMS2 (16), significantly in terms of age (mean (S.D.) 58.1 (10.4) vs the SF-36v2 (15) and the AcroQol (17). The SF-36 is a 55.1 (14.0); tZ1.10, PZ0.32), gender (% female 52 vs 2 generic measure of health status in the form of a 35; c Z1.67, PZ0.20) or age at diagnosis (mean (S.D.) 36-item questionnaire, providing scores on eight 43.8 (11.5) vs 40.7 (17.7); tZ0.84, PZ0.41). domains of functioning and well-being: physical functioning, role physical, role emotional, social Patient demographics functioning, mental health, energy/vitality, pain and general health perception and two broad areas of Details of patient demographics are shown in Table 1. subjective well-being: physical and mental health. Thirty (51.7%) participants were female, 43% were in Scores were compared with normative data for a UK paid employment and 38% were retired. The mean (S.D.)

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Figure 1 Flow chart showing participation in the study from the cohort and reasons for non-participation. age was 58.1 (10.4) years. The mean duration of (nZ2), previous spinal trauma (nZ1) and CVA diagnosed acromegaly was 14.3 (7.1) years, with mean (nZ1). Two patients had MEN 1 comprising hyperpar- (S.D.) age at diagnosis of 43.8 (11.5) years. Forty-seven athyroidism and acromegaly of which one had severe (81%) had controlled acromegaly and 11 (19%) were osteoporosis and multiple low-trauma fractures, con- uncontrolled. tributing to significant musculoskeletal disability and pain. The current presence of musculoskeletal symp- toms and control of acromegaly were not significantly Prevalence of musculoskeletal symptoms related (c2Z0.16, dfZ1, PZ0.69). Of 58 patients, 30 (51.7%) were recalled of musculoske- letal symptoms at the time of diagnosis: this information Use of medical services had been recorded in 20 (66%) medical records. The mean estimated (S.D.) age of onset of musculoskeletal Table 2 shows the medical services consulted for pain by 50 participants was 42 (14.4) (Table 1). musculoskeletal symptoms. Fifty-one (87.9%) had Fifty-two of 58 patients (89.7%) reported current sought help from their primary care physician about musculoskeletal pain. Other disorders contributing to musculoskeletal pain and over half received physiother- musculoskeletal symptoms at the time of the study were apy. Thirty-one had sought complementary therapies ankylosing spondylitis (nZ1), recent mild trauma for their pain including chiropractors, osteopaths and acupuncturists.

Table 1 Participant demographics and duration of uncontrolled acromegaly. Carpal tunnel syndrome (CTS) Characteristic N % Ten (17.2%) had previous decompression surgery. Twenty-three (39.7%) had symptoms at diagnosis. Gender Female 30 51.7 Male 28 48.3 Table 2 Medical services consulted by patients with acromegaly for Employment status musculoskeletal symptoms (NZ58). Full time 17 29.3 Part time 8 13.8 N (%) Running family home 7 12.1 Sickness/disability pension 4 6.9 General practitioner 51 (87.9) Retired early 16 27.6 Orthopaedic surgeon 26 (44.8) Retired normal 6 10.3 Rheumatologist 9 (15.5) Mean (S.D.) Physiotherapy 26 (44.8) Age at study, years 58.1 (10.4) Accident and emergency attendance 4 (6.9) Age at diagnosis of acromegaly, years 43.8 (11.5) Complementary therapists 31 (53.5) Age at onset of musculoskeletal pain 42.0 (14.4) Imaging (XR or MRI) 31 (53.5) (nZ50), years Neurophysiological studies 7 (12.1) Duration of uncontrolled acromegaly, 16.7 (10.4) Joint injections 8 (13.8) years (nZ51) Joint surgery 16 (27.6)

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Eighteen (31%) had current symptoms and 12 (20.6%) Table 3 Mean (S.D.) short form-36 (SF-36) scores in the study had clinical evidence of median nerve compression population, in a normal population of 712 men and women aged when tested by Tinel’s and/or Phalen’s test. 55–59 years (18) and in 48 patients with non-functioning pituitary tumours (19).

Fibromyalgia and non-restorative sleep Mean (S.D.) Mean (S.D.) Mean (S.D.) normal non-function- Sleep disturbance was found to characterize half the study population ing pituitary study population (nZ29, 50%), with half reporting population (18) tumour (19) Z waking unrefreshed (n 30, 51.7%). Eleven (19.0%) Physical functioning 65.0 (29.6) 79.4 (22.9)‡ 79 (21)‡ had been investigated with sleep studies. However, only Role physical 65.7 (31.0) 80.1 (34.9)† 73 (37) 2 (3.5%), one male and one female, had clinical Role emotional 76.6 (28.0) 84.8 (31.3) 78 (36) evidence of fibromyalgia indicated by the presence of Social functioning 76.9 (24.4) 86.9 (21.9)† 86 (20)* more than ten fibromyalgic points. Mental health 73.0 (17.2) 75.9 (17.4) 75 (21) Energy/vitality 51.0 (22.5) 60.3 (20.5)† 57 (23) Pain 60.7 (28.4) 76.7 (25.0)‡ 80 (25)‡ General health 55.4 (21.0) 68.4 (21.6)‡ 66 (25)* Results of examination perception

The main sites of pain reported were in the neck (50% *P!0.05, †P!0.01, ‡P!0.001 for t-test comparison with study population participants), low back (53%), hip (56.9%) and knee scores. (48%). Hip pain was present in 28 patients (48.3%), but restricted hip movement, indicating osteoarthritis was mental health and pain. Variables significantly inde- present in 84.5% of the group. Knee pain was reported pendently associated with the SF-36 domain physical by 33 (56.9%) with objective evidence of knee arthritis function were type of employment, subjective sleep by restricted knee movement in 34.5% and deformity disturbance and presence of musculoskeletal pain. such as swelling in 24%. AIMS 2 scores were worse for the group with There was a reduced range of active cervical move- musculoskeletal pain for all domains except social ment in 77.6%. Limited lumbosacral movement was activity and work, but were only statistically significant present in only 2 (3.4%) including one with ankylosing for pain, P!0.05. Global, physical and psychological spondylitis. The most commonly reported site of pain in AcroQol scores were significantly poorer in the group the upper limb was the shoulder (nZ13, 22%), but fewer with musculoskeletal pain. The duration of uncon- (nZ9, 15.5%) had a reduced range of shoulder move- trolled acromegaly was not significantly associated with ment, indicating probable referred neck pain. Deformi- any AIMS2, AcroQol, or SF-36 questionnaire score. ties of the fingers were observed in 38% of the group.

Questionnaires scores and comparison with Discussion scores from other studies This is the first detailed study of musculoskeletal Table 3 compares SF-36 mean (S.D.) scores from the problems encountered by patients with acromegaly, study population with the population norms for which utilises a systematic rheumatological exami- individuals aged 55–59 from the Oxford Healthy Life nation. We identified those diagnosed with acromegaly Survey (18) and with published results of scores for 48 longer than 5 years in order to evaluate the effects of patients with non-functioning pituitary tumours age 59 long-term and irreversible arthropathy rather than the years (S.D. 12 years) from the Oxfordshire region (19). early reversible arthropathy. The study is limited by These groups were of comparable mean age with our being cross-sectional but provides data on the impact of study group aged 58 (S.D. 10) years. Our study group musculoskeletal problems on quality of life and the SF-36 scores were poorer than those reported by these services utilized by these patients. While the SF-36 and patients in all domains and significantly lower in the AcroQol have been used before (9), this study is the first physical functioning, social functioning, pain and to report on AIMS2 scores in acromegaly. general health perception domains. SF-36 scores were Biermasz et al. presented data on 118 acromegalic significantly lower than the scores in the general patients in long-term remission reviewing the preva- population for all domains except role emotional and lence of self-reported joint problems along with other mental health with a P value!0.001. morbidity (9). Joint complaints were especially perceived Table 4 compares questionnaire scores between study to contribute to reduced quality of life. As with our study, patients with and without musculoskeletal pain for the the presence of joint problems was unrelated to normal SF-36, the AIMS2 and the AcroQol. Those with GH parameters or active disease duration. musculoskeletal pain, forming the much larger group, Our response rate was 67%. There were no significant scored lower for all SF-36 domains except role differences between participants and non-participants emotional but reached statistical significance at in terms of age, gender or age at diagnosis, although P!0.05 only for the domains of physical functioning, participants tended to be older and female. The presence

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Table 4 Questionnaire scores in acromegalic patients with and without musculoskeletal pain.

With pain Without pain Mann–Whitney N Mean (S.D.) N Mean (S.D.) P value

SF-36 domain Physical functioning 52 62.5 (30.1) 6 86.3 (12.4) 0.040 Role physical 52 63.5 (31.60) 6 85.4 (14.6) 0.131 Role emotional 52 76.6 (28.2) 6 76.4 (28.1) 0.832 Social functioning 52 76.2 (24.9) 6 83.3 (20.4) 0.558 Mental health 52 71.4 (17.0) 6 86.7 (12.9) 0.033 Energy/vitality 52 49.4 (22.1) 6 65.6 (22.3) 0.153 Pain 52 56.6 (27.1) 6 96.3 (5.7) 0.000 General health perception 49 54.6 (19.6) 6 62.3 (32.0) 0.803 AIMS2 Mobility 50 1.04 (1.54) 5 0.20 (0.27) 0.282 Walking and bending 49 2.38 (2.48) 5 1.10 (1.03) 0.241 Hand and finger function 50 0.38 (0.82) 5 0 (0) 0.256 Arm function 49 0.45 (1.11) 5 0 (0) 0.217 Self-care 50 0.40 (1.36) 5 0 (0) 0.619 Household tasks 50 0.50 (1.34) 5 0 (0) 0.432 Social activity 49 4.06 (1.82) 5 4.6 (2.1) 0.504 Support from family 46 2.03 (2.48) 4 0.47 (0.94) 0.164 Arthritis pain 48 3.01 (2.89) 5 0.08 (0.17) 0.002 Work 24 1.12 (1.58) 3 1.67 (1.44) 0.532 Level of tension 48 2.30 (1.68) 5 1.33 (2.1) 0.112 Mood 48 1.90 (1.39) 5 1.48 (1.39) 0.524 AcroQol Global score 52 59.1 (16.0) 6 75.8 (13.2) 0.018 Physical score 52 59.9 (20.9) 6 79.7 (13.7) 0.028 Psychological score 52 58.5 (17.3) 6 73.5 (13.8) 0.047 of musculoskeletal pain was reported in 90% of months (20), with the risk of unforeseen drug interactions participants, a higher proportion than the 70% reported and Rao et al. found 90% of 146 rheumatology patients in other studies (1, 2). This may reflect recruitment by had used CAM at some time (21). written invitation asking the patient to participate in a Similarly to previous reports, 17% had undergone study of musculoskeletal problems, although it was carpal tunnel release prior to diagnosis of their disease specified that those without should also participate. (9). CTS, although classically associated with the initial Nevertheless, the number with joint problems is high. phase of acromegalic arthropathy, was present in 31% Despite having acromegaly, a serious and chronic of this group, indicating it may be a longer term disease, more than half were in paid employment or problem requiring further treatment. running a family home and fewer than 10% relied on a A high proportion of patients reported neck pain and sickness or disability pension. had reduced range of cervical movement. In some, neck Study numbers did not allow sub-analysis of whether pain was referred to the shoulder or elbow, resulting in types of treatment for acromegaly (surgical, radio- joint pain without evidence of local arthritis. Low back therapy, medical or combination) or the need for pain was also reported but a modified Schober index was replacement therapy with hydrocortisone, oestrogen not found to be a useful indicator of reduced mobility. or progesterone or thyroxine, was associated with Hand joint pain with nodal changes of osteoarthritis was rheumatological outcome. common and the AIMS2 questionnaire demonstrated Only 66% of those recalling musculoskeletal symptoms functional hand impairment in these patients. Knee pain at diagnosis had this information recorded in their medical was the most commonly reported joint problem and notes, perhaps indicating less attention paid to this aspect clinical evidence of hip osteoarthritis the commonest of their symptoms at clerking. Most patients reporting examination finding. Referred pain from hip to knee may current musculoskeletal pain had sought help from their account for some reported knee pain. general practitioner but only half had been referred for Studies of sleep apnoea in acromegalics have demon- physiotherapy. Almost 60% had sought complementary strated both upper respiratory obstruction and central therapies for their pain. The use of complementary and components (14). Even those without sleep apnoea have alternative medicine (CAM) is common in rheumatologi- a profound reduction in the amount of rapid eye cal patients. Holden et al. reported 44% follow-up movement (REM) sleep time (22). Non-organic muscle rheumatology outpatients in three UK centres had used pain is attributed to non-restorative sleep in rheumatoid herbal or over the counter remedies in the previous 6 patients (23). In view of these sleep disturbances in

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Downloaded from Bioscientifica.com at 09/25/2021 11:42:05AM via free access 592 A Miller and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158 acromegaly, it was anticipated that a number of their patients in this study. This study was funded by a participants might have evidence of fibromyalgia. grant from the Oxford Health Services Research However, despite the high incidence of sleep disorders Committee. Ethical approval was received from the and reports of non-restorative sleep, very few had Oxford Research Ethics Committee. fibromyalgia, refuting non-organic pain as an important contributor to musculoskeletal problems in acromegaly. The questionnaires demonstrate an association between musculoskeletal disease and reduced quality of References life in acromegalic patients. In the study by Biermasz et al. 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