Rheumatologic manifestations of acromegaly

INTRODUCTION — Acromegaly is a rare disorder characterized by excess secretion of growth hormone (GH) and its principal mediator, insulin-like growth factor (IGF) 1, whose production is stimulated by GH. An abnormal excess of GH is most commonly the result of a pituitary adenoma. A range of somatic and metabolic changes can occur in patients with acromegaly. Among these is an arthropathy, which is frequent in this condition and sometimes severe and disabling. The arthropathy may, in some cases, be a presenting feature of acromegaly [1,2].

The joint disorders associated with acromegaly are discussed here. The causes, other clinical manifestations, diagnosis, and treatment of acromegaly and GH excess in children and adolescents (pituitary gigantism) are reviewed in detail separately. (See "Causes and clinical manifestations of acromegaly" and "Diagnosis of acromegaly" and "Treatment of acromegaly" and "Pituitary gigantism".)

PATHOPHYSIOLOGY — Growth hormone (GH) and insulin-like growth factor (IGF) 1 are essential for normal growth, differentiation, and repair of cartilage and bone. Excess GH and IGF-1, which are characteristic of acromegaly, lead to an arthropathy that resembles osteoarthritis (OA) but is distinguished from idiopathic disease by its radiographic appearance and an increased prevalence among patients with acromegaly. The pathophysiology of acromegalic arthropathy is not fully understood. A common hypothesis is that there are two stages of arthropathy, with the first stage partially reversible on treatment [3,4]:

●In the first stage, excess GH and IGF-1 cause proliferation of articular chondrocytes and increased matrix production. This leads to thickened and abnormal articular cartilage and widening of the joint spaces (the latter can often be appreciated on radiographs). GH also affects connective tissue, promoting the growth of periarticular structures, which results in ligamentous laxity and joint instability. Synovial hypertrophy also occurs.

●In the second stage, cartilage damage occurs. Abnormalities in repair mechanisms, presumably due to excess GH, results in over-proliferation of regenerating fibrocartilage, which may become calcified and result in subsequent osteophyte formation. Subchondral cysts may also occur. Cartilage thickening may persist, but some patients may go on to have cartilage loss and joint space narrowing [5].

A study of 67 acromegalic patients in long-term remission found an association between pretreatment levels of IGF-1 and the risk of OA of hip, hands, and cervical spine, although an association with pretreatment GH concentrations was not observed [6]. However, other research has identified an association between baseline elevation of both GH and IGF-1 with the arthropathy [7]. Patients with acromegaly also appear to have an increased risk of musculoskeletal conditions arising outside of the joint. Studies have described increased rates of carpal and cubital tunnel syndrome, trigger finger, and calcification of ligaments in patients with acromegaly [8-10].

EPIDEMIOLOGY — A degenerative arthritis, often referred to as osteoarthritis (OA) or secondary OA, is substantially more common in patients with acromegaly compared with the general population. Estimates on the prevalence of this arthritis among patients with acromegaly varies widely, from 30 to 70 percent or greater [2,11]. Arthropathy in acromegaly affects both males and females. In some studies [12,13], but not others [6,7], arthropathy is more frequent in females. The prevalence increases with age [7]. Definitions of acromegalic arthropathy vary widely from study to study, with some utilizing symptom prevalence versus radiographic features for diagnosis. Duration of acromegaly and disease activity at the time of diagnosis, treatment protocol, and age differences among the study populations likely account for the wide variation reported in the literature.

Early studies noted joint symptoms in the majority of patients with acromegaly [14]. However, a Belgian nationwide registry study of 418 patients with acromegaly in 2003 to 2004 reported symptoms of arthropathy in 46.7 percent [5]. In a retrospective study of 324 acromegalic patients presenting between 1981 and 2006, symptoms of arthropathy were noted in approximately 40 percent at diagnosis [15], with no significant difference between cohorts presenting in the early and later years of that study. A nationwide Danish cohort study of 405 acromegalic patients diagnosed between 1991 and 2010 showed the prevalence of arthropathy to be approximately double that of controls, both during the 3 years prior to diagnosis and from 1 to 30 years after diagnosis [7]. However, the definition of arthropathy in patients and controls was not given.

In a 1994 report of 500 patients with acromegaly, OA was noted in approximately 45 percent of cases, but whether this was radiographic or symptomatic was not described [16]. The prevalence of radiographic OA in patients with acromegaly is typically higher than symptomatic OA, similar to the general population [6]. In a detailed study of 89 patients with adequate long-term control of acromegaly, radiographic evidence of OA was present at one or more joint sites in 99 percent of patients, while symptoms of pain and stiffness were reported in 72 percent of patients [17]. OA was significantly more common and occurred at a younger age than in the control group. A study in 2022 confirmed these findings, with radiographic evidence of OA in 90 percent of patients, nearly all of whom (96 percent) had OA in two or more joint areas [18].

The epidemiology of acromegaly is described separately. (See "Diagnosis of acromegaly", section on 'Epidemiology'.)

CLINICAL MANIFESTATIONS

Symptoms and physical findings — The primary symptom of the arthropathy in acromegaly is joint pain, particularly with activity [11,19-22]. The disease is typically polyarticular, and joint tightness, crepitus, and effusions have all been described. Hyperlaxity of the joints and spine can also occur, often followed by stiffness due to a combination of degenerative changes and thickening of subcutaneous tissues. In the hands, the symptoms may be complicated by coexistent carpal tunnel syndrome and related paresthesia, or by trigger finger [8]. Similar to primary OA, the synovial fluid is noninflammatory, but several radiographic and clinical features can be distinguished in acromegalic arthropathy (table 1).

Spinal pain is common. Pain in the cervical and lumbar spine has been reported in over 60 percent of patients in long-term remission, while radiographic OA is seen at those sites in 91 and 82 percent, respectively [23]. In a 2004 study of patients with active acromegaly, spinal pain occurred frequently, with 37 percent reporting neck pain, 17 percent reporting thoracic pain, and 50 percent reporting lumbar pain [24]. Kyphoscoliosis was reported in 21 percent of patients, although it is not clear from this study what proportion was due to degenerative change versus vertebral fractures. A subsequent study in 2019 described 58 patients with acromegaly and found vertebral fractures, predominantly thoracic, in 13.8 percent of patients. Meanwhile, thoracic kyphosis (of >50 degrees severity) was identified in 36.8 percent of patients, and scoliosis in 34.5 percent, suggesting that abnormal spinal curvature was not due to vertebral fractures in all such patients [25]. Abnormalities in bone density and skeletal fragility, including an increased risk of vertebral fractures, are discussed in detail separately. (See "Causes and clinical manifestations of acromegaly", section on 'Bone and joints'.)

Typical findings in acromegaly include widening of the hands and feet, with thickening of the fingers, toes, and soft tissues [11]. Changes develop gradually together with other manifestations of disease [26]. Disease affects the large joints more than small joints, both weightbearing and nonweightbearing.

The sites of involvement, peripherally and axially, are variable:

●The peripheral joints most commonly affected symptomatically are the knees (50 percent), hips, shoulders, and hands (all three sites: 40 percent), while involvement of the elbows, ankles, and feet is less common [18,22].

●Spinal pain and radiographic changes in the axial skeleton are frequent in both active and controlled disease [23,24]. Features of diffuse idiopathic skeletal hyperostosis (DISH) may be seen in 20 percent, correlating with impaired glucose tolerance [24]. (See "Diffuse idiopathic skeletal hyperostosis (DISH)".)

●Temporomandibular pain and malocclusion were reported in one-third of patients in one series [21].

●The acromegalic rosary is a palpable but not necessarily visible enlargement of the costochondral junctions. This finding occurred in 26 out of 27 subjects in one series [27].

The relationship between the severity of joint involvement and the severity and duration of acromegaly is uncertain. Arthropathy appears to be more common in older patients with a longer duration of disease [19,20]. However, there is wide variability, and arthropathy is the presenting complaint in some patients. Symptoms often persist after control of the excess hormone production. As an example, a study of 118 acromegalic patients in remission showed that 77 percent had self-reported joint problems, particularly of the hip and/or knee [12].

The diagnosis of acromegaly is often delayed, allowing the arthropathy to progress before treatment begins. A Spanish epidemiologic study reported that patients described symptoms of acromegaly an average of five years before diagnosis [28], while a smaller British prevalence study [29] described a delay of 1.5 to 15 years (median 4.5 years) before diagnosis. In this latter study, 28.6 percent of patients had joint symptoms at diagnosis.

Radiographic progression of the arthropathy may not always reflect the progression of clinical symptoms. A prospective study of 31 patients with controlled acromegaly over a 9-year period showed significant radiographic progression of arthropathy in hips, knees, hands, and spine, although the progression of clinical symptoms was very variable and less frequent [30]. Higher baseline Kellgren and Lawrence scores at the hip predicted progression of hip OA in this study, while active disease duration, treatment modality, and pretreatment insulin-like growth factor (IGF) 1 levels did not.

Imaging findings — Characteristic changes on plain radiography include widening of joint spaces due to cartilage overgrowth and thickening of the soft tissues, which occurs in the early stages (image 1). The radiographic changes of the arthropathy in acromegaly are not necessarily associated with clinical symptoms and vary according to the stage of the arthropathy. The joint changes may progress to cartilage loss and features of degenerative joint disease, which are eventually indistinguishable from OA in many patients (image 2 and table 1). There can be persistence of the characteristic radiographic findings of wide joint spaces, despite long-term control of acromegaly [17]; these changes may be associated with more self-reported pain [31]. In addition to these changes in the joints, thickening of the heel pad is often seen.

Radiology of the hip may show osteophytosis with preserved joint spaces or with joint space narrowing. Joint space narrowing occurs in approximately a third of patients with radiographic OA of the hip associated with acromegaly [32]. Similarly, in the knee, osteophytosis and preservation of joint spaces is common, but approximately half of those with features of OA of the knee will have joint space narrowing [32]. In the shoulder, there may be osteophytosis with normal or widened joint spaces, but loss of joint space or flattening of the humeral head occurs in a minority of patients [22].

Chondrocalcinosis has also been reported in association with acromegaly [33,34]. It is not clear, however, if this is a feature of acromegaly or a coincidental finding, as only rare case reports exist.

Changes of the arthropathy are also seen with magnetic resonance imaging (MRI). In a study that compared active and controlled acromegalic patients with controls with primary OA of the knee, patients with acromegaly had fewer cysts and bone marrow lesions but a similar prevalence of osteophytosis and cartilage defects [4]. Cartilage thickness was greater in acromegalic patients compared with primary OA, and there was a small but significant increase in cartilage thickness in those with active acromegaly compared with controlled acromegaly.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

●Diagnosis – Acromegalic arthropathy should be suspected in patients with known acromegaly who present with joint pain and stiffness that worsens with activity. The diagnosis can be made most confidently in a patient with a confirmed diagnosis of acromegaly and is supported by appropriate clinical and radiographic features of disease (such as early findings of joint space widening and proliferative changes of bone, including prominent osteophytes). In later disease, the radiographic features may unfortunately be indistinguishable from primary osteoarthritis (OA). Acromegalic arthropathy should also be considered in patients presenting with OA at a young age, involving atypical joints, associated with joint space enlargement on radiographs, in association with soft tissue enlargement and/or other clinical features of acromegaly. (See "Causes and clinical manifestations of acromegaly", section on 'Soft tissue and skin'.)

●Diagnostic evaluation – Diagnostic testing should include plain radiographs of symptomatic joints. MRI and ultrasound are not routinely used in diagnosis of acromegalic arthropathy but may be of value if symptoms are suggestive of other problems. For example, MRI can be used when clinically indicated to investigate coexistent pathology such as meniscal or ligament problems in the knee, and ultrasound may be helpful in evaluating coexistent shoulder tendon problems. The diagnostic evaluation of acromegaly is described separately. (See "Diagnosis of acromegaly".)

●Differential diagnosis – The arthropathy resembles generalized OA in that both upper and lower extremity and nonweightbearing joints can be affected, joint space narrowing can be present, and osteophyte formation is common. However, joint radiographs of the arthritis of acromegaly in the earlier stages show joint space widening and may show more osteophyte formation and less joint space narrowing at the hip and knee, compared with those of patients with primary generalized OA (table 1) [35].

Symptoms of pain and weakness in the extremities due to carpal tunnel syndrome and a peripheral neuropathy (not limited to median neuropathy) may also occur in patients with acromegaly and are described separately. (See "Causes and clinical manifestations of acromegaly", section on 'Soft tissue and skin'.)

TREATMENT AND PROGNOSIS — Some symptoms of the arthropathy and much of the cartilaginous thickening may improve with treatment of the acromegaly [21,36]. A decrease toward normal articular cartilage thickness has been documented ultrasonographically following 12 months of treatment with either octreotide [37] or lanreotide [38]. It is not clear whether medical or surgical treatment has more of an effect on progression of arthropathy. In one study, despite biochemical control, patients who received medical treatment with somatostatin analogues showed more progression of osteophytes and joint space narrowing than patients who were surgically cured [39]. Another retrospective study of 150 patients showed that good biochemical control, achieved using surgical and a variety of pharmacologic treatment, reduced the risk of diabetes and cardiovascular disease, but the risk of arthritis of spine, hips, hands, and knees appeared unaffected [40]. Another study from 2009 showed no effect of the type of treatment on arthropathy [6]. Despite this conflicting data, early diagnosis and good disease control are advised to maximize any reversible aspects of the arthropathy. (See "Treatment of acromegaly".)

Unfortunately, once bone damage has occurred, the arthritis is irreversible and tends to progress despite adequate control of growth hormone (GH) secretion, although there may be large variations between individuals [30,41]. In this setting, standard measures for the treatment of any degenerative arthropathy apply, including medications for pain relief, physical and occupational therapy, and, if necessary, joint replacement, as described in detail separately. (See "Overview of the management of osteoarthritis".)

Weight control is also advised, as a higher body mass index (BMI) may be associated with the progression of lower-limb osteoarthritis (OA) in acromegalic patients in remission, and also with more articular symptoms [41,42]. Intraarticular glucocorticoid injection appeared to be ineffective in one study [22]. It is also important to assess patients for other concurrent musculoskeletal conditions that may be amenable to intervention (eg, meniscal tears, rotator cuff tendinopathy, periarticular bursitis, etc).

The arthropathy is not associated with increased mortality [43] but can represent one of the most powerful predictors of reduced quality of life and depression [42,44,45]. As an example, a study of 58 patients with acromegaly over a five-year period found that 90 percent reported musculoskeletal pain associated with reduced quality of life and poor sleep, with 88 percent consulting their general practitioner for pain and over half consulting complementary medicine therapists [46].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Joint and spine disorders, which can be considered to be a type of secondary osteoarthritis (OA), are common in acromegaly and may dominate the clinical picture. These effects appear to be due to acceleration of the normal growth process by excess growth hormone (GH) and insulin-like growth factor (IGF) 1, which are essential for normal growth, differentiation, and repair of cartilage and bone. (See 'Pathophysiology' above.)

●Clinical manifestations – The main manifestations of the arthropathy in acromegaly include joint pain, particularly on activity. Joint pain and tightness, crepitus, effusions, and hyperlaxity of the joints and spine may occur. Spinal pain is common, and kyphoscoliosis may be seen. Vertebral fractures may contribute to a percentage of patients with kyphosis. The peripheral joints most commonly affected are the knee, shoulder, hip, and hands. Axial involvement may affect any portion of the spine but is most common in the lumbar region, and features of diffuse idiopathic skeletal hyperostosis (DISH) may be present. (See 'Symptoms and physical findings' above.)

●Imaging findings – The radiographic changes of the arthropathy in acromegaly vary according to stage. Widening of joint spaces due to cartilage overgrowth and thickening of the soft tissues occurs in the early stages (image 1), progressing to osteophyte formation, cartilage loss, and degenerative joint disease, which eventually may be indistinguishable from primary OA (image 2). In addition, thickening of the heel pad is often seen. (See 'Imaging findings' above.)

●Treatment – The symptoms of the arthropathy and the cartilaginous thickening may improve with treatment, but in many patients symptoms persist. In addition, once bone damage has occurred, the arthritis is irreversible and tends to progress despite adequate control of GH secretion. In this setting, standard measures for the treatment of any degenerative arthropathy apply. (See 'Treatment and prognosis' above.)

●Prognosis – The arthropathy of acromegaly has a significant impact on quality of life. It is important to assess routinely for musculoskeletal problems and to provide appropriate multidisciplinary treatment. (See 'Treatment and prognosis' above.)