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Musculoskeletal Effects of the Recombinant Human IGF-I/IGF Binding Protein-3 Complex in Osteoporotic Patients with Proximal Femoral Fracture: A Double-Blind, Placebo-Controlled Pilot Study

Katholieke Universiteit Leuven (S.B., R.B., P.B., D.V.), B-3000 Leuven, Belgium; University of Maine (C.R.), Bangor, Maine 04401; Celtrix Pharmaceuticals (A.S., M.M., D.R., S.A.), Santa Clara, California 95054; and Limburgs Universitair Centrum (J.L., J.R., P.G.), B-3590 Diepenbeek, Belgium

Address all correspondence and requests for reprints to: Steven Boonen, M.D., Ph.D., Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine, Katholieke Universiteit Leuven, University Hospitals K.U. Leuven, Brusselsestraat 69, B-3000 Leuven, Belgium. E-mail: . steven.boonen{at}uz.kuleuven.ac.be

Abstract

The administration of recombinant human IGF-I complexed with its predominant binding protein IGF binding protein-3 (rhIGF-I/IGFBP-3) may allow the safe administration of higher doses of IGF-I than can be accomplished with rhIGF-I alone. The aim of this randomized, double-blind, placebo- controlled pilot study was to evaluate the short-term safety and musculoskeletal effects of rhIGF-I/IGFBP-3 in older women (aged 65–90 yr) with recent hip fracture. Within 72 h after the event, 30 patients received continuous administration of either placebo (n = 10), 0.5 mg/kg·d rhIGF-I/IGFBP-3 (n = 9), or 1 mg/kg·d rhIGF-I/IGFBP-3 (n = 11). Treatment was administered by sc infusion through a portable mini-pump for a total of 8 wk after hip fracture surgery, with patient follow-up to 6 months after surgery. Efficacy evaluations included a contralateral hip bone density determination, markers of bone turnover (including serum osteocalcin and urinary excretion of N-telopeptide), grip strength, and tests of functional ability. During the administration of rhIGF-I/IGFBP-3, mean serum levels of IGF-I significantly (P < 0.001) increased from 83 ng/ml to 289 ng/ml (0.5 mg/kg·d) and 393 ng/ml (1 mg/kg·d), respectively. Both doses were well tolerated, and no hypoglycemia or other therapy-induced side effects were observed. After an initial loss of hip bone density after hip fracture surgery, patients treated with 1 mg/kg·d rhIGF-I/IGFBP-3 regained a substantial portion of their femoral bone mass. At 6 months postfracture (4 months after the 2-month infusion), they showed a statistically not significant decrease from baseline in hip bone density (-2.6%, P = 0.53). Placebo-treated patients, on the other hand, failed to regain lost bone: at 6 months postfracture, bone density in the placebo group had declined by 6.1% (P = 0.04). Additionally, in patients treated with 1.0 mg/kg·d rhIGF-I/IGFBP-3, grip strength had increased from baseline by 11.4% by the end of the study (P = 0.04) whereas patients on placebo lost 11.6% from baseline (P = 0.16). This increase in muscle strength in the high-dose group was associated with a positive effect on functional recovery. We conclude that a 2-month infusion of rhIGF-I/IGFBP-3 in patients with recent hip fracture is feasible, safe, and well tolerated. Analyzing the effects on bone mass, muscle strength, and functional ability, we observed beneficial trends. In the context of a small exploratory study, these findings should be interpreted with caution, but they support the need for future trials to further assess the therapeutic potential of rhIGF-I/IGFBP-3 in elderly subjects with osteoporosis.

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