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

Disclosures

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

In This Article

Discussion

In this long-term prospective study, significant radiographic OA progression was observed at all studied joint sites in long-standing controlled acromegaly patients over the course of 9 years. By contrast, the course of clinical joint symptoms per joint site was highly variable, varying from significant deterioration of hand function to unchanged lower limb complaints. Different risk factors for radiographic progression were assessed, but solely higher KL scores at the baseline study visit predisposed for hip OA in this cohort.

Acromegalic arthropathy appears to be mainly a degenerative joint disorder, like primary OA, although some characteristics are specific to acromegaly.[8–11] The most predominant radiographic feature of acromegalic arthropathy is severe OP, which is frequently observed in combination with joint space widening, reflecting cartilage hypertrophy.[6,11] These structural changes persist despite achievement of long-term remission.[12,40] In only a subset of patients, JSN is observed (a predominant feature of primary OA), particularly in patients with higher cumulative GH exposure in time, delayed postoperative cure, or ongoing smoldering disease activity.[13,23] Severe OP has been associated with increased self-reported pain in primary OA and acromegaly, which is not the case for JSN, since cartilage is not innervated.[5,7,13,52,53] Arthropathy has been hypothesized to be mechanistically linked to the observed osteopathy in acromegaly, which might explain the presence of OP.[7,54] Additionally, a hypothesized pathophysiological mechanism for acromegalic arthropathy is the commitment of mesenchymal stem cells toward chondrocytes instead of osteoblasts, resulting in cartilage formation and therefore joint space widening.[55] The exact mechanisms, however, remain unknown.

To our knowledge, this is the only investigation of the long-term course of arthropathy in a cohort of patients with long-term controlled acromegaly. Radiographic progression of OA was observed in all patients at at least one joint site during 9.1 years of follow-up despite biochemical remission. The highest progression rates were observed in facet and hand joints, whereas the progression rate in the knees was lowest. In our previous 2.6-year follow-up study describing 58 controlled patients, radiographic OA was assessed using another scoring method: the Osteoarthritis Research Society atlas.[56] In that study, progression of JSN ranged from 15% (hip) to 40% (hand) and progressive OP was observed in 26% (hip) to 28% (hand) of patients; axial OA was not assessed.[21] In the present evaluation, using KL scores, a scoring method combining OP and JSN assessment, similar 2.6-year radiographic progression rates were observed in the hands and hips, whereas almost no radiographic progression was observed in the knees in the first 2.6 years. At all joint sites, further structural joint deterioration was observed in the second follow-up period, indicating continuous deterioration of radiological OA during prolonged remission.

Because increasing age is an established acromegaly-independent risk factor for OA progression, comparing the radiographic progression observed in acromegaly with the radiographic OA course in the general population and primary OA cohorts might provide valuable insights. Studies describing the course of radiographic OA in the general population are scarce, showing variable rates of progression, although comparison between these cohorts and our cohort of acromegaly patients is hampered by variable follow-up durations and different scoring methods. Radiographic progression was observed in the knees in 21.8% of patients, and in the hips in 8.7% of patients, respectively, in a cohort based on the general Dutch population during 6.6 years of follow-up.[57] In the Framingham study, a United States–based general population cohort, incident hand OA was observed in 34.6% of females 33.7% of males,[58] and progressive knee OA was observed in 24.2% of males and 31.8% of females over 8.1 years of follow-up.[59] In a cohort of Dutch generalized primary OA patients with hand OA, 6-year progression of OP and JSN was present in 44.9% and 25.8% of patients, respectively, and, notably, radiological progression was not linked to clinical progression.[51] Moreover, during a 6-year follow-up, 74.4% had radiographic progression of pre-existing knee OA, whereas 28.8% of patients developed radiographic knee OA in the aforementioned cohort.[60] Therefore, long-term progression rates of acromegalic arthropathy appear equal to (knees), or higher than the general population (hands and hips), and lower (hands and knees) compared to generalized primary OA cohorts. Evidently, progression rates are additionally dependent on joint site.

The etiology of OA is multifactorial, with different risk factors being associated with different joint sites. In primary OA, hip and hand OA are associated with systemic and genetic risk factors, whereas knee OA is more related to local, biomechanical factors, for example, BMI or previous knee trauma.[61] In acromegaly patients, the effects of pathologically high GH and IGF-1 levels appear to differ per joint site as well. In the present study, the only identified risk factor for long-term radiological progression was the baseline severity of hip OA (higher KL scores increasing hip OA progression). Other risk factors, including parameters reflecting (previous) GH/IGF-1 excess, could not be established, which is in contrast with our previous short-term follow-up study, in which associations between short-term radiographic progression and higher age, higher baseline IGF-1 SDS, and delayed postoperative cure were found.[21] Based on the scarce available data, parameters reflecting (previous) disease activity, and therefore hormonal excess exposure, are hypothesized to play an important role in OA development and progression in early disease remission, whereas during prolonged remission, progression of radiological acromegalic arthropathy might become more dependent on preexisting structural joint deformities, irrespective of the degree of previous GH/IGF-1 exposure. By contrast, the adequate statistical power to replicate previous identified risk factors might not have been achieved because of the small, possibly heterogeneous sample size (see the following sections). Nevertheless, the high OA prevalence and significant radiographic progression rates that persist after remission reflect the long-standing negative musculoskeletal effects in acromegaly, necessitating adequate clinical awareness and assessment of acromegalic joint disease in these patients.

In contrast to the demonstrated radiographic progression of OA, the course of joint symptoms showed great intraindividual variability. Solely significant deterioration of hand function, as measured by the AUSCAN questionnaire function subscale, and cylinder grip strength was observed, whereas pain and stiffness scores remained relatively stable over time. Joint complaints of the lower limb assessed by the WOMAC questionnaire showed significant variation over time, without overall progression. Previously, self-reported joint complaints and mainly axial arthropathy were shown to negatively influence QoL significantly, limiting physical functioning and psychological well-being.[4] By contrast, radiological OA was not associated with impaired QoL.[4] In another large cohort including active and controlled acromegaly patients, motor disability measured by self-reported questionnaires negatively correlated with QoL, with female patients and patients with higher BMI being most at risk.[62] Furthermore, progression of joint symptoms was not related to progression of radiographic alterations in this study cohort, a phenomenon previously reported both for acromegaly and primary OA patients, for which the underlying mechanisms remain to be elucidated.[4,51] Based on QoL being particularly influenced by joint symptoms and the current absence of sensitive biomarkers to monitor acromegalic arthropathy adequately, we advise focusing on the clinical course of arthropathy, with consideration of structural, radiographic alterations.

Compared to available reference curves of hand complaints, total AUSCAN scores in acromegaly patients appeared similar to the general Dutch population, although variation was high, with several outliers above the 90th percentile.[63] With respect to lower-limb complaints, WOMAC pain and function disability scores, both at baseline and after 9 years of follow-up, of our acromegaly cohort appeared significantly lower compared to a Dutch cohort of patients with early hip or knee OA complaints of comparable age, whereas stiffness scores were comparable.[64] These findings suggest that, at least at the lower limb, long-term controlled acromegaly patients have less subjective symptoms than the general population, which might be explained by a different pathophysiology of acromegalic arthropathy compared to primary OA with potentially different experiences of joint symptoms due to neurological alterations. Moreover, a potential selection bias might have occurred with inclusion of patients with fewer joint symptoms (see the following sections).

The optimal management of acromegalic arthropathy is unknown. To date, pharmacological interventions that prevent the onset of OA, or delay structural disease progression, are not available. Stringent control of GH and IGF-1 hypersecretion is the cornerstone in the management of acromegalic arthropathy, since previous studies showed more cartilage loss and more progression of arthropathy in patients with smoldering disease.[13,21] Next to general lifestyle advice beneficial for primary OA, such as weight loss and preventing traumatic injuries, current treatment options are mainly symptomatic: analgesics (paracetamol or nonsteroidal anti-inflammatory drugs), intra-articular corticosteroid injections, or joint replacement therapy in case of treatment-resistant joint complaints. Unfortunately, the potential beneficial effects of these treatment modalities have not been formally evaluated in acromegalic arthropathy. Additionally, the role of physical therapy in managing acromegaly patients with joint disease, and the optimal timing of joint replacement surgery, have not been studied to date.

This study has several limitations. The most important limitation is the small population size. However, this is a single-center cohort study with 9 years of follow-up among patients with a rare disease, which depended on the availability of consenting patients, resulting in a limited number of patients at the second follow-up visit. Although nonparticipants did not differ from participants regarding acromegaly disease parameters or joint symptoms at baseline, the included patients had relatively low AUSCAN and WOMAC scores at follow-up as compared to our previous publications, indicating that this patient cohort was "healthy." In this respect, because of the homogeneity of the studied subset, the discrimination of risk factors for progression was hampered. Another limitation is the absence of a control group (compared with, eg, participants from the general Dutch population with 10 years of radiographic follow-up) to address the effect of aging, an established risk factor for OA progression. Another limitation is that radiological OA scoring methods, including KL scores, are not validated in acromegaly, and do not include joint space widening, which is a predominant feature of acromegalic arthropathy. By contrast, we believe that this study describes a unique cohort of acromegaly patients with prolonged follow-up in remission, and a protocolized radiological assessment by high-quality, senior observers, exploring the long-term course of acromegalic arthropathy.

In summary, significant progression of radiographic arthropathy was observed in patients with long-term, well-controlled acromegaly, whereas the course of joint symptoms varied per joint site, showing deterioration of hand function. The radiographic progression in prolonged remission appears to be less dependent on acromegaly disease parameters, but more on preexistent degenerative changes. Further studies are needed to examine optimal acromegaly-specific assessment methods and a treatment strategy for arthropathy.

processing....