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Pegvisomant-Induced Serum Insulin-Like Growth Factor-I Normalization in Patients with Acromegaly Returns Elevated Markers of Bone Turnover to Normal

Department of Diabetes and Endocrinology (C.P.), The Ipswich Hospital, Ipswich IP4 5PD, United Kingdom; Department of Endocrinology and Metabolism (M.K.), University Hospital of Odense, Odense DK 5000, Denmark; Departments of Clinical Biochemistry (L.H.) and Medical Research Laboratories (A.F.), Aarhus University Hospital, Aarhus DK 8000, Denmark; and Department of Endocrinology (P.J.T.), Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Dr. Peter J. Trainer, Department of Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom. E-mail: Peter.Trainer{at}man.ac.uk.

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28–78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)₂ vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 ± 76 to 242 ± 28 µg/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)₂ vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)₂ vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.

A.F. is supported by grants from the Danish Medical Research Council (Grant 9700592), the Novo Foundation, the Aage Louis-Hansen Memorial Foundation, the Nordic Insulin Foundation, the Eva and Henry Frænkels Memorial Foundation, and the Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration (Grant 9600822). P.J.T. and C.P. have received research funds from Sensus Drug Development Corporation and Pharmacia UK.

Abbreviations: 1,25-(OH)₂ vit D, 1,25-Dihydroxy vitamin D; 25-(OH) vit D, 25-hydroxy vitamin D; 11ßHSD1, 11ß hydroxysteroid dehydrogenase; BAP, bone-related alkaline phosphatase; CTx, C-terminal cross-linked telopeptide of type I collagen; CV, coefficient of variation; iPTH, intact PTH; NTx/Cr ratio, urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio; OC, osteocalcin; OHP, hydroxyproline; PICP, carboxyterminal propeptide of type I collagen; PIIINP, procollagen III amino-terminal propeptide; PINP, type I procollagen amino-terminal propeptide; SMS, somatostatin.

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