Progression of Acromegalic Arthropathy in Long-Term Controlled Acromegaly Patients

9 Years of Longitudinal Follow-Up

Iris C.M. Pelsma; Nienke R. Biermasz; Wouter R. van Furth; Alberto M. Pereira; Herman M. Kroon; Margreet Kloppenburg; Kim M.J.A. Claessen


J Clin Endocrinol Metab. 2021;106(1):188-200. 

In This Article

Materials and Methods

Study Design and Patient Selection

Study Protocol. This study was designed as a prospective, longitudinal follow-up study in long-term, well-controlled acromegaly patients with a median follow-up duration of 9.1 years and included 3 study visits, at baseline, and after a median follow-up duration of 2.6 and 9.1 years, respectively. In brief, patients completed standardized questionnaires at all study visits (see following sections), fasting blood samples were obtained to assess actual GH and IGF-1 levels, and all patients underwent radiographic OA assessment by conventional radiographs of the hands, knees, hips and spine (see following sections). This study was approved by the medical ethics committees of the Leiden University Medical Center and all participants gave their written informed consent.

Patients. Details of the present long-term follow-up study have been published recently.[23] Briefly, in 2007, all acromegaly patients visiting the outpatient clinic of the Center of Endocrine Tumors Leiden of the Leiden University Medical Center who were in long-term biochemical remission for 2 or more years were invited to participate in a cross-sectional study on joint and bone complications of acromegaly. Remission was achieved by surgery, radiotherapy, pharmacological treatment, or a combination of these treatment modalities (see following sections). Eighty-nine patients were included for the baseline study Visit,[12] and 58 patients (65%) agreed to participate in a first follow-up study visit following a median follow-up interval of 2.6 years (range, 2.3–2.9 years). After a median follow-up of 9.1 years from baseline (range, 8.8–10.6 years), 31 patients (53.4%) were included in the second follow-up study visit. Reasons for not participating were non–musculoskeletal-related health problems (N = 4), lack of time (N = 2), loss to follow-up (N = 9), psychological reasons (N = 1), being abroad (N = 1), or for unknown reasons (N = 10). Demographic and disease characteristics, including self-reported hand, knee, or hip OA symptoms using validated questionnaires (see following sections), were comparable between participants and nonparticipants, except for higher BMI among nonparticipants (P = .019) (see Supplementary Table 1[24]).

At the outpatient clinic, all acromegaly patients are evaluated on an annual basis providing clinical follow-up data. Since 1977, transsphenoidal pituitary surgery was the primary treatment modality in our center. Prior to 1985, patients received adjuvant treatment in the form of radiotherapy, and from 1985 onward patients received adjuvant somatostatin (SMS) analogues. Patients could receive primary medical treatment with long-acting SMS analogues starting in 1998, which results in controlled disease in more than 90% of patients.[25] For SMS analogue-resistant acromegaly, pegvisomant (PegV) is prescribed, resulting in normalized IGF-1 levels in almost all patients from 2003 onward.[26,27]

Study Parameters

Acromegaly Disease Parameters. As described in our previous publications, in all patients, acromegalic disease activity and the function of other pituitary axes were assessed on an annual basis, or more frequently when applicable.[4,5,7,21–23] Definitions of disease remission varied prior to the baseline visit and during this long-term follow-up study, with a minimum duration of 12 years. Acromegaly was considered in remission when IGF-1 levels (based on age-adjusted SD scores [SDS]), and glucose-suppressed GH levels were normal, independent of the treatment modality used for achievement of remission (ie, surgery, radiotherapy, and pharmacological treatment). Duration of active disease was calculated using the estimated date of onset of the disease and the date of normalization of serum IGF-1 following treatment.[28,29] Furthermore, the dates of biochemical remission and the second follow-up visit were used to calculate duration of disease remission.

Assessment of Pituitary and Gonadal Function. Hypopituitarism was defined as clinically significant hormone deficiencies of 1 or more axes requiring supplementation according to the following definitions:[30,31] (1) thyrotropin deficiency: free thyroxine 4 levels below the reference range (< 10 pmol/L); (2) adrenocorticotropic hormone deficiency: insufficient increase in cortisol levels (< 0.55 μmol/L) following corticotropin-releasing hormone stimulation or insulin tolerance test, (3) hypogonadism: testosterone concentration of less than 8.0 nmol/L for more than 1 year in male patients, and prolonged untreated amenorrhea accompanied by serum estradiol concentrations of less than 70 nmol/L or natural menopause for female patients. Patients were considered eugonadal when hypogonadism was treated adequately (ie, hormone replacement therapy for less than 1 year following the start of hypogonadism). Furthermore, female patients were considered eugonadal if normal spontaneous menstrual cycles occurred or if estrogen hormone replacement therapy or oral contraceptives were used. GH deficiency, assessed following clinical or biochemical suspicion, was defined and treated with an individualized dose of recombinant GH according to current guidelines.[32–34]

Biochemical Assays. From 2005 onward, serum GH levels were assessed using a nationally harmonized GH assay, first on the Immulite 2500/2000XPi immunoanalyzer (until November 3, 2017), and later the IDS-iSYS analyzer, was used with a harmonization factor of 1.02.[35] Serum IGF-1 concentrations were measured using immunometrics (Immulite 2500 system, Diagnostic Products Corporation) following 2005, with intra-assay variations at mean plasma levels of 8 and 75 nmol/L of 5.0% and 7.5%, respectively. From 2017 onward, IGF-1 levels have been measured using the IDS-iSYS immunoanalyzer. SDS were used to express IGF-1 levels, using λ-μ-σ–smoothed reference curves for age- and sex-related normal levels.[36,37] The assessment of serum GH and IGF-1 levels prior to 2005 is described in detail in our previous publications.[4,5,7,21–23,28]

Questionnaires. A standardized questionnaire concerning demographic data, medical history, and symptoms and signs of OA was completed by all patients at all study visits, during which OA-specific questionnaires on self-reported joint symptoms compromising the subscales pain, stiffness, and functional limitations also were filled out. The Australian/Canadian Osteoarthritis Index (AUSCAN) questionnaire was used for evaluation of hand symptoms,[38] rating all items on a 5-point Likert scale ranging from 0 (none) to 4 (extreme) within a 48-hour time frame. Total scores ranged from 0 to 20 for pain, 0 to 4 for stiffness. and 0 to 36 for joint function. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess pain, stiffness, and disability of the lower limb.[39] Scores ranged from 0 to 100 using a 100-mm visual analog scale format, with 0 representing the absence of complaints and 100 as the worst score possible.

Performance Tests. As described previously in more detail,[40] the lumbar flexion index, defined as the range of motion of the lumbar spine, was assessed at all study visits.[41] In addition, at each study visit, cylinder grip strengths of both hands were assessed 2 times to the nearest kilogram using a cylinder grip meter, using the average of the 2 measures for the analyses.[42,43]

Definition of Progression of Joint Symptoms. Clinically relevant change in hand symptoms was based on previously defined minimum clinically important improvement (MCII) cutoff values of 1.49 and 1.25 for the pain and function subscales.[44] For the stiffness subscale, MCII cutoff values are not available.

Progression of lower limb symptoms was defined as an increase in self-reported pain, stiffness, and function above predefined cutoff values of 9.7 mm for pain, 10.0 mm for stiffness, and 9.3 mm for the function subscale. These cutoff values were based on the minimum perceptible clinical improvement (MCPI), a method previously used to define treatment response in OA.[45]

Radiographic Protocol. According to standardized protocols with a fixed film-focus distance and fixed joint position, conventional radiographs of the hands (dorsovolar), knees (posterior-anterior [PA] in weight-bearing/fixed semi-flexed and lateral), hip (PA), lumbar (PA and lateral), and cervical spine (anterior-posterior [AP] overview, AP transbuccal and lateral) were obtained from all participating patients. Knee radiographs were made in fixed-flexion.[46] A single experienced radiology technician performed the radiographic assessment for all patients at all 3 study visits.

Assessment of Radiographic Progression. After blinding for patient characteristics, all radiographs were semiquantitively scored according to the Kellgren and Lawrence (KL) scoring system by 2 experienced scorers (K.C. and H.K.) in consensus, paired in chronological order.[47–49] The KL score is a composite score, ranging from 0 to 4, evaluating the presence of OP, JSN, sclerosis, and degenerative cysts to determine OA severity in a specific joint. Radiographic OA in a particular joint site is defined as a KL score of 2 or more, reflecting mild OA. Scored joints in the hands were the distal interphalangeals, proximal interphalangeals, metacarpal-phalangeals, interphalangeal joint of the thumb (Ips), and first carpometacarpal joints. Furthermore, medial and lateral tibiofemoral joints of the knees were scored. Cervical and lumbar spine were evaluated both for discus degeneration and facet OA, scoring cervical vertebrae 2 to 7 (C2-C7), lumbar vertebrae 1 to 5 (L1-L5), and sacral vertebra 1 (S1). Total scores were calculated by adding the left and right sites of the peripheral joints. The maximum total KL scores were 120 for the hands, 8 for the knees, 8 for the hips, 40 for discus degeneration, and 40 for the facet joints. Axial OA was defined as a combination of discus degeneration and facet OA, resulting in a maximum total score of 80. Radiographic data of the baseline and first follow-up visit were partially published previously.[21,40]

Reproducibility of the KL scores were assessed by the intraclass correlation coefficient based on the repeat examination by the team in consensus of 4 to 6 radiographs (depending on the joint site) that were selected at random. Reproducibility scores were 0.91 for the hands and spine, 0.92 for the knees, and 1.00 for the hips.

Definition of Radiographic Osteoarthritis Progression. Radiographic progression was assessed at the axial level (ie, combination of facet OA and discus degeneration) and at the peripheral joint sites level. Radiographic progression was defined as the change in KL score above the smallest detectable change (SDC),[50] calculated using the mean change and SD of mean change based on the repeat radiographs, combining both OA progression—in patients with prevalent radiographic OA at baseline—and incident OA in patients without OA features at baseline. For the hips, SDC was 1.00, resulting in a cutoff of 1 KL point for progression. For the knees, hands, and spine, KL score cutoff for progression was 2 points, because SDC values were 1.31, 1.17, and 1.15, respectively. A new total joint replacement in a patient without radiographic endstage disease (KL score 4) at the previous study visit was also considered as progression in that particular knee or hip joint. One patient with a bilateral knee prosthesis at baseline was excluded from the final analyses of knee OA progression because further progression at this joint site was unmeasurable.

Statistical Analysis

Data analysis was performed using SPSS for Windows, version 25.0 (SPSS Inc). The intraclass correlation coefficient was calculated using a 2-way mixed model for single measurements. Data are presented as mean ± SD, mean (95% CI), median (interquartile range [IQR]), or N (%), unless otherwise specified. Changes over time were analyzed in multiple ways: (1) using either t tests, repeated-measures analysis of variance, Mann-Whitney U, or Friedman tests, (2) using cumulative probability plots.[22,51] Risk factor analyses were performed using either χ 2 tests, Fisher exact tests, binary logistic regression analyses, or linear regression analyses. Association analyses were performed using Spearman rank correlation. A P value less than .05 was considered significant.