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.
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.
Boonen
Steven
S
Katholieke Universiteit Leuven, Belgium. steven.boonen@uz.kuleuven.ac.be
Rosen
Clifford
C
Bouillon
Roger
R
Sommer
Andreas
A
McKay
Malcolm
M
Rosen
David
D
Adams
Steven
S
Broos
Paul
P
Lenaerts
Jan
J
Raus
Jef
J
Vanderschueren
Dirk
D
Geusens
Piet
P
D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D004311:Double-Blind Method; D004338:Drug Combinations; D005240:Feasibility Studies; D005260:Female; D005264:Femoral Fractures / Q000209:etiology*; D005500:Follow-Up Studies; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects*; D010024:Osteoporosis / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D010865:Pilot Projects; D010919:Placebos; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use
D004338:Drug Combinations; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I