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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 2121-2125
Copyright © 1998 by The Endocrine Society

Original Studies

Reversibility of Joint Thickening in Acromegalic Patients: An Ultrasonography Study

Annamaria Colao, Paolo Marzullo, Gianfranco Vallone, Valeria Marinò, Massimo Annecchino, Diego Ferone, Davide de Brasi, Raffaele Scarpa, Pasquale Oriente and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology (A.C., P.M., V.M., D.F., G.L.), Radiology (G.V., M.A.), and Rheumatology (D.D.B., R.S., P.O.), Federico II University of Naples, Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via S. Pansini 5, 80131 Naples, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Axial and peripheral arthropathy affects the majority of patients with acromegaly, being a leading cause of morbidity and functional disability. Treatment with octreotide (OCT) improves symptoms and signs of acromegalic arthropathy, but objective detection of structural changes in bone and cartilage has not been reported to date.

This open prospective study was designed to evaluate the effect of a long term treatment with OCT on acromegalic arthropathy assessed by ultrasonography examination. Articular cartilage thicknesses of shoulder, wrist, and knee as well as sizes of heel tendons were measured in 30 acromegalic patients (18 with active and 12 with inactive disease) and 18 sex-, age-, and body mass index-matched healthy subjects.

The thicknesses of shoulder, wrists and knees articular cartilages and that of heel tendons were significantly increased in patients with active acromegaly compared to those in healthy subjects (P < 0.01). With the exception of shoulder cartilage, significant increases in wrist and knee cartilages (P < 0.01) and right and left heel tendon sizes (P < 0.05) were found in patients with active compared to those with inactive disease. After 6 months of OCT treatment, a significant decrease in shoulder, wrist, and left knee articular cartilage was found (P < 0.001). No significant change was recorded in right knee cartilage or heel tendon size. The decrease in thickness of shoulder and wrist cartilages was more pronounced than that measured at the level of left knee (26.3 ± 3.3% and 27.2 ± 4.2% vs. 14.2 ± 4.2%, respectively; P < 0.05).

Ultrasonography is able to reveal articular involvement in acromegalic patients and may be useful to monitor the effect of treatment.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ARTICULAR manifestations of acromegaly have been recognized since Marie’s classical description of the disease in 1886 (1). Spinal and peripheral joint abnormalities in patients with acromegaly may be severely disabling. Joint morphology has been scarcely investigated, and some previous data are available (2, 3). Arthropathy in acromegaly affects both axial and peripheral sites and is generally noninflammatory (4, 5). In later stages of the disease, it frequently develops features of osteoarthritis (2, 3, 4, 5). Controversial data have been reported on the possibility that acromegalic arthropathy may be modified by GH-suppressing treatment (6, 7, 8). Treatment with octreotide (OCT) was shown to improve symptoms and signs of acromegalic arthropathy (9). Mild to moderate improvements in pain, crepitus, and range of motion were observed in the majority of patients treated with OCT (9). However, whether objective structural improvement of bone and cartilage occurs is still unknown.

Ultrasonography (USG) has become increasingly important in clinical practice. This noninvasive imaging technique has three main advantages: it is of low cost, it is widely available with easy performance, and it is less time-consuming. As far as articular diseases are concerned, the strength of the USG method clearly lies in the evaluation of periarticular soft tissue structures, such as the joint capsule or tendons, especially when exudative processes are present (10).

The aim of this study was to evaluate the effects of a long term treatment with OCT on acromegalic arthropathy assessed by USG examination.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty acromegalic patients (15 women and 15 men; age range, 20–67 yr) were included in this open prospective study. The diagnosis of acromegaly and the status of the disease were based on clinical, hormonal, and radiological features, as previously reported (11). Eighteen patients had active disease [GH, 33.3 ± 6.3 ng/mL; insulin-like growth factor I (IGF-I), 593.4 ± 37.7 ng/mL], whereas the remaining 12 had inactive disease after surgery and/or radiotherapy or treatment with OCT (GH, 1.1 ± 0.3 ng/mL suppressed below 1 ng/mL after oral administration of 75 g glucose; IGF-I, 152.4 ± 17.9 ng/mL). Eighteen healthy subjects, sex, age, and body mass index matched with the patients in active disease, served as the control. The presumed duration of acromegaly was assessed by comparison of patients photographs taken during 1- to 2-decade span and by patient’s interviews to date the onset of acral enlargement. The duration of disease was assumed as the interval between the clinical onset and the time of treatment. For patients in inactive disease, the period of GH normalization was also calculated. The patients’ profile at study entry are shown in Table 1Go.


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  		Table 1. Patients’ profile at study entry

 
Treatment protocol

Twelve patients in active disease were treated with OCT (Sandostatina, Novartis, Milan, Italy) for 6 months. OCT was initially administered at a dose of 0.15 mg in six patients and 0.3 mg daily in four patients, according to patients’ compliance during the acute test (0.1 mg, sc), as previously reported (12). Subsequently, the dose of 0.3 mg/day was maintained throughout the follow-up in six patients, whereas it was increased up to 0.6 mg daily in two patients to obtain GH/IGF-I suppression, improvement of clinical signs and symptoms, and/or tumor shrinkage. At study entry, plasma IGF-I levels were assayed twice in a single sample, whereas serum GH was calculated as the mean of a 6-h blood sampling (0800–1400 h, with every 30 min sampling). During treatment, the final GH level was calculated as the average value from at least three blood samples collected, at 15-min intervals, 2 h after OCT administration. At this time point, plasma IGF-I concentrations were assayed as single sampling.

USG imaging technique

The USG study was performed using a SONORA LOGIC 500 MD apparatus by means of a 7.5-megahertz transducer, preliminarily covered with ultrasound transmission gel (Acquasonic, Parker Laboratory, Orange, NJ) or by a spacer pad for curve structures that are usually difficult to measure. The articular cartilage of right and left knees was measured at the suprapatellar space with the joint bent at 90°. The articular cartilage of the shoulder was measured in transversal sections with the arm adducted to the trunk. The articular cartilage of the wrist was measured at the radiocarpal joint. Because all subjects were right-handed, in this study only the sizes of right shoulder and wrist were measured. All USG measurements were performed by two operators (G.V. and M.A.) who were blind with respect to the patients’ treatments and/or disease activities.

Assays

Serum GH levels were assayed by RIA using kits provided by Radim (Pomezia, Italy); the normal GH range was less than 5 ng/mL, and the sensitivity was 0.2 µg/L. Plasma IGF-I levels were assayed after ethanol extraction by immunoradiometric assay using kits provided by Diagnostic System Laboratories (Webster, TX); in our laboratory the normal IGF-I ranges in 20- to 30-, 31- to 40-, 41- to 50-, and over 50-yr-old subjects were 110–502, 100–494, 100–303, and 78–258 ng/mL, respectively.

Statistical analysis

Data are reported as the mean ± SEM. ANOVA followed by Newman-Keuls test and Student’s t test for paired data were used where appropriate. Linear correlation analysis was used to evaluate correlation between variables. The significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
USG findings in acromegalic patients compared to controls

The thicknesses of articular cartilages of shoulder, wrist, and knees as well as right and left heel tendon sizes were significantly increased in patients with active acromegaly compared to those in healthy subjects (Table 2Go). With the exception of shoulder cartilage, significant increases in wrist and knee cartilages (P < 0.01) and right and left heel tendon sizes (P < 0.05) were found in patients with active compared to those with inactive disease (Table 2Go). No significant difference was found between patients with disease duration less or greater than 10 yr as far as USG articular findings were concerned except for the wrist (Fig. 1Go). In the entire series of patients, no significant correlation was found between USG findings and circulating GH and IGF-I levels (data not shown).


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  		Table 2. Ultrasound findings in patients with active and inactive acromegaly and in healthy subjects

 


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  		Figure 1. USG measurement of the thicknesses of shoulder, wrist, and knee cartilages and of heel tendons in acromegalics with disease duration less than or greater than 10 yr. *, P < 0.05 vs. patients with disease duration less than 10 yr.

 
Effect of long term OCT treatment on articular involvement in acromegalic patients

A significant decrease in the thicknesses of shoulder, wrist, and left knee articular cartilages was found after 6 months of OCT treatment (Fig. 2Go). By contrast, although a slight decrease was noted, no change in right knee cartilage (4.4 ± 0.3 mm) and right (5.5 ± 0.2 mm) and left (5.3 ± 0.3 mm) heel tendon sizes was found. The reduction of shoulder and wrist cartilages, two nonweight-bearing joints, was notably more pronounced than that of knees (26.3 ± 3.3% and 27.2 ± 4.2% vs. 14.2 ± 4.2%, respectively; P < 0.05). At the end of the 6-month OCT treatment, notable improvements in joint pain and active and passive articular mobility were recorded in all patients as well as in weakness, soft tissue swelling, hyperidrosis, headache, and other signs and symptoms of the disease.



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  		Figure 2. Individual values (left) and mean ± SEM (right) for the thickness of shoulder (top), wrist (middle), and left knee cartilages (bottom) measured by USG in 12 patients with acromegaly before and 6 months after treatment with OCT.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most relevant result of this study is that USG is able to measure joint thickness of acromegalic patients and may be useful to monitor the effect of OCT treatment. Arthropathy, which includes articular involvement and enthesopathy, affects most patients with acromegaly; it is a leading cause of morbidity and functional disability. Degenerative disease is the most common manifestation, and crepitus on exam is the most common finding. In a large series of acromegalics, at least 60% had minor joint complaints, and 16% had severe joint problems (5). The pathogenesis of arthropathy involves both GH excess and secondary degenerative changes. The GH excess induces systemic and local IGF-I production, and in turn, IGF-I promotes DNA synthesis, cell replication, proteoglycan, and glycosaminoglycan synthesis in the articular chondrocytes (13). The natural history of acromegalic arthropathy starts with hypertrophy of cartilage and soft tissue. At this stage there is a relative paucity of objective findings at radiology, which often documented widening of the joint spaces and periarticular soft tissue hypertrophy (13). Osteoarthritis is often found in acromegalic patients with a long history of untreated disease. It has been suggested that hypertrophied hyaline cartilage of acromegaly prematurely degenerates possibly as a result of its poor perfusion and minor trauma (14). The degeneration in cartilage tissue seems to occur despite growth and cartilage repair that are known to be stimulated in vivo by GH and IGF-I (15, 16). By USG, a significant increase in the thickness of both weight-bearing and nonweight-bearing cartilages was documented in acromegalic patients compared to that in sex-, age-, and body mass indexed-matched healthy subjects. Although joint size was significantly reduced compared to that in patients with active disease, articular and periarticular soft tissue hypertrophy was also noticeable in patients with inactive disease for at least 2 yr. Despite the evidence that the long standing GH/IGF-I hypersecretion (<10 yr) causes a narrowing of articular spaces (13), no difference in shoulder and knee articular thickness was found between patients with disease duration more or less than 10 yr. Only wrist cartilage thickness was significantly smaller in patients with a longer disease duration. By contrast, enthesopathy, another common finding of acromegalic arthropathy, was documented on the basis of the increase in both heel tendons only in the patients with active disease. In patients with inactive disease for 2–21 yr, the thickness of heel tendons was similar to that observed in healthy subjects.

Medical treatment with OCT is widely recognized as effective in suppressing circulating GH and IGF-I levels in acromegaly (17, 18). OCT treatment at a dose of 0.3–0.6 mg/day for 6 months significantly reduced the thickness of shoulder and wrist and also of the left knee, whereas it did not modify the sizes of right knee and both heel tendons. The percent decrease in the thicknesses of shoulder and wrist were greater than that recorded for knees, probably because they are nonweight-bearing joints. The lack of effect on right knee thickness could depend on the heavier weight charge on the right lower limb in right-handed people. In fact, in the present study the reversibility of acromegalic arthropathy was evaluated as early as after 6 months of OCT treatment. The possibility that a further reduction of joint thickening and enthesopathy could occur after a longer period of treatment cannot be ruled out. On the other hand, in patients with inactive acromegaly of at least 2-yr duration, heel tendon size was similar to that recorded in healthy subjects, whereas a small thickening of shoulder, wrist, and knee articular sites is still noticeable. Dons et al. (14) suggested that lowering the GH level by any form of currently available treatment does not arrest the evolution of the arthropathy once a significant build-up of abnormal cartilage has occurred. However, anecdotal reports suggest that therapy to lower GH production improves the arthropathy of acromegaly (6, 7, 8, 9, 19). By contrast, other studies reported no significant changes (3, 5). Joint complaints seldom resolved after pituitary surgery (20) or after OCT treatment (8). The examination of joint radiographs indicates that in the process of developing severe arthropathy, patients will experience a decrease in both weight-bearing and nonweight-bearing joint spaces within the first 5–10 yr after therapy (14), pointing out that a long period is needed for the development of complete arthropathy in acromegaly. Similarly, a long period of GH/IGF-I suppression could be necessary to revert cartilage overgrowth and/or degeneration or enthesopathy.

In conclusion, the results of the present study demonstrate that USG of articular spaces is useful to measure the degree of cartilage thickening and to monitor the effect of OCT treatment. Articular and periarticular soft tissue hypertrophy of shoulder and wrist, two nonweight-bearing joints, was partially reversed by suppressing GH and IGF-I levels for 6 months, and a significant decrease was noticeable in the articular space of the left knee. The analysis performed in patients with inactive acromegaly for at least 2 yr suggested that a longer period of treatment can be useful to improve enthesopathy or arthropathy of weight-bearing joints, such as knees.

Received January 22, 1998.

Revised February 23, 1998.

Accepted February 27, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Marie P. 1886 Sur deux cas d’acromégalie. Rev Med. 6:297–299.
  2. Waine H, Bennet GA, Bauer W. 1945 Joint disease associated with acromegaly. Am J Med Sci. 209:671–678.
  3. Kellgren JH, Ball J, Tutton GK. 1952 The articular and other limb changes in acromegaly. Q J Med. 21:405–423.[Free Full Text]
  4. Bluestone R, Bywaters E, Hartog M, Holt PJL, Hyde S. 1971 Acromegalic arthropathy. Ann Rheum Dis. 30:243–258.[Free Full Text]
  5. Detenbeck L, Tressler H, O’Duffy J, Randall RV. 1973 Peripheral joint manifestations of acromegaly. Clin Orthop. 91:119–127.
  6. Holt P. 1981 Locomotor abnormalities in acromegaly. Clin Rheum Dis. 7:689–709.
  7. Johanson NA, Vigorita VJ, Goldman AB, Slavati EA. 1983 Acromegalic arthropathy of the hip. Clin Orthop. 173:130–139.
  8. Lacks S, Jacobs RP. 1986 Acromegalic arthropathy: a reversible rheumatic disease. J Rheumatol. 13:634–636.[Medline]
  9. Layton MW, Fudman EJ, Barkan A, Braunstein EM, Fox IH. 1988 Acromegalic arthropathy: characteristics and response to therapy. Arthritis Rheum. 31:1022–1027.[Medline]
  10. Manger B, Kalden J. 1995 Joint and connective tissue ultrasonography-a rheumatologic bedside procedure? Arthritis Rheum. 38:736–742.[Medline]
  11. Colao A, Merola B, Ferone D, Lombardi G. 1997 Acromegaly. J Clin Endocrinol Metab. 84:2777–2781.
  12. Colao A, Ferone D, Lastoria S, et al. 1996 Prediction of efficacy of octreotide therapy in patients with acromegaly. J Clin Endocrinol Metab. 81:1356–1362.
  13. Barkan A. 1997 Acromegalic arthropathy and sleep apnea. J Endocrinol 155:S41–S44.
  14. Dons RF, Rosselet P, Pastakia B, Doppman J, Gorden P. 1988 Arthropathy in acromegalic patients before and after treatment: a long-term follow-up study. Clin Endocrinol (Oxf). 28:515–524.[Medline]
  15. Chrisman OD. 1975 The effect of growth hormone on established cartilage lesions. Clin Orthop. 107:232–238.
  16. Sledge CB. 1973 Growth hormone and articular cartilage. Fed Proc. 32:1503–1505.[Medline]
  17. Lamberts SWJ, van Der Lely AJ, de Herder WW, Hofland J. 1996 Octreotide. N Engl J Med. 334:246–254.[Free Full Text]
  18. Melmed S, Ho K, Klibanski A, Reichlin S, Thorner M. 1995 Recent advances in pathology, diagnosis and management of acromegaly. J Clin Endocrinol Metab. 80:3395–3402.[CrossRef][Medline]
  19. Lamberts SWJ, Uitterlinden P, Verschoor L, van Dongen KL, del Pozo E. 1985 Long-term treatment of acromegaly with the somatostatin analogue SMS 201–995. N Engl J Med. 313:1576–1580.[Abstract]
  20. Rolfsema F, Vandulken H, Frolich M. 1986 Long-term result of transsphenoidal pituitary microsurgery in 60 acromegalic patients. Clin Endocrinol (Oxf). 23:555–565.



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