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Endocrine Care |
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.
BY ANY MEASURE, proximal femoral fracture is the most devastating complication of osteoporosis. The mortality rate in patients with hip fracture is 12–20% higher than in persons of similar age and gender who have not suffered a fracture (1). Of those who survive the operative intervention for an osteoporotic hip fracture, less than one third are restored to their prefracture functional state and either require some form of ambulatory support (50%) or even institutionalized care (20%) (2). Therefore, it is imperative that we continue to refine our treatment approaches, with the goal of improving the outcome. Recent longitudinal data reveal that, after proximal femoral fracture, elderly women lose bone and muscle mass at an increased rate (3). Among other factors, this loss of musculoskeletal integrity is likely to have a major impact on the outcome of rehabilitation and on the risk of fracture recurrence (4). It is tempting to speculate that selected anabolic agents might be able to modify this process by enhancing bone and muscle mass and, thus, facilitate the postsurgical rehabilitation and reduce the risk of developing recurrent fractures.
Current strategies for the treatment of osteoporosis rely almost exclusively on agents whose pharmacological actions are primarily antiresorptive. These include oestrogen, calcitonin, and bisphosphonates. Although each of these constrains bone loss and may achieve modest increases in bone mass, none completely reverses the bone deficits of osteoporotic patients, and none improves muscle strength. Considerable interest exists, therefore, in developing drugs to stimulate bone formation, including recombinant growth factors such as IGF-I (rhIGF-I). Because of the potent anabolic effects of IGF-I on bone and muscle tissue (5, 6, 7, 8), rhIGF-I has potential as a drug to enhance musculoskeletal integrity in osteoporotic patients. The aim of this randomized, double-blind, placebo-controlled pilot study was to evaluate the short-term safety and musculoskeletal effects of a systemically administered complex of recombinant IGF-I and its most abundant binding protein, IGF binding protein-3 (rhIGF-I/IGFBP-3) in severely osteoporotic older women with recent (trochanteric or cervical) hip fracture. This complex was selected because animal studies had indicated that rhIGF-I/IGFBP-3 may have an improved safety and efficacy profile compared with rhIGF-I alone (9).
Materials and Methods
Study subjects
Women admitted to the Department of Traumatology at the participating sites following a fracture of the proximal femur were recruited consecutively. To be eligible for participation, women had to be over 65 yr of age, to be previously ambulatory, and to have suffered a fall resulting in a radiologically confirmed first hip fracture. Cervical and trochanteric fractures were defined from the surgical report.
Patients were excluded if they met any of the following criteria: 1) having been admitted with a pathologic fracture or a fracture resulting from trauma other than a fall; 2) having sustained a previous hip fracture; 3) known unresected or metastatic cancer; 4) dementia or disorientation resulting in inability to cooperate with the examiner in the performance of study assessments; 5) renal failure as evidenced by serum creatinine higher than 17 mg/liter; 6) participation in any experimental therapy study within the last 30 d; or 7) concomitant treatment with GH or anabolic steroids.
The study was performed according to the Helsinki declaration and was approved by the institutional review boards at all participating centers. The nature of the trial was explained to the patients, and their written informed consent was obtained.
Study drug
The protein complex rhIGF-I/IGFBP-3 (SomatoKine; Celtrix Pharmaceuticals, Inc., San Jose, CA) is manufactured by fermentation (each protein separately) of rhIGF-I and rhIGFBP-3 in genetically engineered Escherichia coli bacteria containing the DNA encoding for each of the human proteins. The purification of both proteins is achieved by column chromatography. Both proteins are substantially purified separately before combining them for complex formation. The rhIGF-I/IGFBP-3 complex is formed in a 1:1 molar ratio of rhIGF-I to rhIGFBP-3, corresponding to the naturally occurring protein complex. Cation exchange column chromatography is used to purify the complex.
Experimental design
The subjects were randomized equally in a double-blind fashion to three treatment groups, which received placebo or rhIGF-I/IGFBP-3 at 0.5 mg/kg·d or 1.0 mg/kg·d (corresponding with 0.1 mg/kg·d and 0.2 mg/kg·d IGF-I, respectively). The study drug was administered by sc infusion, initiated within 48 h after surgery with the use of the CADD-1 ambulatory infusion pump (model 5100 HFX; SIMS Deltec, Inc., St. Paul, MN). The infusion was given continuously. All patients continued the sc infusion for a total of 8 wk (56 d) of treatment. The infusion site was changed at intervals of 48 h or less by a nurse who visited the patients at home. No calcium or vitamin D supplements were given.
Before the first study drug administration and throughout the 8-wk infusion period, patients were physically examined and blood samples were obtained at regular intervals (on d 1, 3, and 7, and at wk 2, 4, and 8). Follow-up examinations were performed at 12, 16, and 24 wk after admission (4, 8, and 16 wk after withdrawal of treatment, respectively), which included physical assessment, biochemical measurements, and bone densitometry.
Biochemical measurements
Venous blood samples for determination of IGF-I and IGFBP-3 were collected immediately before the first study drug administration and at 24, 72, and 168 h (7 d) after initiation of the sc infusion. Additional measurements of IGF-I and IGFBP-3 were performed at wk 2, 4, 8, 12, and 24. Serum levels of IGF-I were measured using a competitive binding RIA (Endocrine Sciences, Inc., Calabasas Hills, CA). The sensitivity of the assay was 10 ng/ml.
At screening, on d 3 and 7, and at wk 2, 4, 8, 12, and 24, blood samples were obtained for complete blood and chemistry profile including serum creatinine, glucose, calcium, phosphate, albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. These analyses were performed by standard methods. On d 1 of study drug administration, additional blood for determination of glucose was obtained at 2, 8, and 16 h.
Immediately before the first administration of study drug or placebo, and at wk 2, 4, 8, 12, and 24, blood and urine samples were obtained to assess serum levels of procollagen peptide and osteocalcin (OCA) and urinary excretion of deoxypyridinoline and type I collagen cross-links of N-telopeptide. Serum levels of C-terminal propeptide of type I collagen were determined by ELISA (Endocrine Sciences, Inc.). The sensitivity of the assay was 2.4 ng/ml. Serum levels of OCA were determined by RIA (Endocrine Sciences, Inc.). The assay has a sensitivity of 0.5 ng/ml. Urine levels of N-telopeptides were determined by ELISA (Endocrine Sciences, Inc.). The assay is sensitive to 20 pmoles bone collagen equivalent/ml. Urine levels of deoxypyridinoline were determined with a competitive enzyme immunoassay in a microtiter stripwell format (Endocrine Sciences, Inc.). The sensitivity of the assay was approximately 3 nM.
Bone mass measurements
Bone mineral density (BMD) assessments were performed by dual-energy x-ray absorptiometry within 5 d after surgery and at wk 4, 8, 12, and 24. Dual-energy x-ray absorptiometry measurements were performed using the Hologic QDR-4500 scanner (Hologic, Inc., Waltham, MA). Standard positioning was used with anterior-posterior scanning of the contralateral proximal femur. With our equipment, the precision of these measurements in elderly women is less than 2% at the proximal femur (10).
Functional assessments
Isometric grip strength was evaluated at the nondominant side with the Jamar 1 dynamometer (TEC Inc., Clifton, NJ) at wk 2 (baseline values), 4, 8, 12, and 24. Three measurements of strength were taken, and the mean of these values was recorded as grip strength. The short-term reproducibility of this measurement in elderly women is 1.2% (11). In addition to the measurement of muscle strength, (neuro)muscular function was evaluated by a previously reported questionnaire (12) and by a number of physical performance tests. Because the ability to rise independently from a standardized armless chair had been to shown to be predictive of hip fracture risk in elderly women (13), this parameter was selected as functional outcome measure.
Adverse experiences
Subjects were instructed to report any unwanted signs, symptoms, injuries, illnesses, or other medical events that occurred during the study and were queried about such experiences at each visit. These were classified as adverse experiences regardless of whether they seemed to be related to the investigational treatment. Physical examinations (including weight, height, heart rate, and blood pressure) were performed at each clinic visit. For purposes of safety monitoring, hematology and serum chemistry were performed at periodic intervals, as indicated above. Any abnormalities were assessed by the investigators.
Statistical evaluation
The comparability of the three treatment groups at baseline was assessed by one-way ANOVA. The baseline values were set at 100%, and all subsequent measurements were expressed as a percentage of these values. For each treatment arm, changes vs. baseline were tested by means of a one-sample t test for matched pairs. Differences between the three treatment groups were investigated with a one-way ANOVA. Contrasts were used to explore pairwise treatment differences. When no differences were observed, groups were combined to increase the number of observations. A longitudinal analysis was used to model mean changes. The longitudinal evaluation was performed by a last carried forward analysis. All reported P values are two sided. The nominal significance level was set at 0.05. All statistical analyses were conducted with the use of SAS software (SAS Institute Inc., Cary, NC).
In view of the explorative nature of this pilot study, it was anticipated that the sample size might be insufficient to demonstrate statistically significant differences between groups. The a priori efficacy hypotheses were that administration of rhIGF-I/IGFBP-3, compared with placebo, would result in 1) increased total hip bone density, 2) increased grip strength, and 3) enhanced functional performance as assessed by the ability to rise from a standardized armless chair.
Results
Baseline characteristics
Subject characteristics, the biochemical parameters, and the results of the bone density and grip strength measurements are shown in Table 1
. Analysis of baseline variables showed no significant differences. In 90% of the study population, (contralateral) total hip bone density was more than 2.5 SD below the mean for young adult women (T-score less than -2.5).
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Of the 33 women who were enrolled, 30 completed all examinations. No patients left the study because of therapy-induced side effects. All subjects completed the full planned 8 wk of dosing.
Adverse events
Various potential adverse events were reported during the trial, including fatigue and constipation (Table 2). No subjects required treatment with concomitant medications for these symptoms, and none of these events was considered to be drug related. Mild erythema was noted at the sc infusion site in all subjects receiving drug at any dose level. No patients on rhIGF-I/IGFBP-3 experienced hypoglycemia during the course of the study. One woman with severe ischemic heart disease died while being treated for pneumonia.
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During the administration of rhIGF-I/IGFBP-3, mean serum levels of IGF-I significantly (P < 0.001) increased from 90 ng/ml to 236 ng/ml (0.5 mg/kg·d) and from 92 ng/ml to 342 ng/ml (1 mg/kg·d), respectively, as shown in Fig. 1. Within 4 wk after discontinuation of the infusion, circulating levels of IGF-I had returned to baseline values in 0.5 mg/kg·d-treated patients (P = 0.96), but not (yet) in the patients treated with 1 mg/kg·d (P = 0.02). Compared with placebo, both 0.5 mg/kg·d and 1 mg/kg·d rhIGF-I/IGFBP-3 were associated with significantly higher levels of serum IGF-I at 24 and 72 h and at 1, 2, 4, and 8 wk (P < 0.001 at all time points). At wk 12 and 24, IGF-I values in rhIGF-I/IGFBP-3-treated patients were not statistically different from those treated with placebo (data not shown). Patients treated with 1 mg/kg·d had higher levels of IGF-I than those on 0.5 mg/kg·d (P < 0.01 at all time points).
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Figure 2 shows the average changes in serum OCA (A) and urinary N-telopeptide (B) during the study. Biochemical markers of bone formation and resorption increased in all groups after hip fracture surgery. According to the longitudinal analysis, subjects treated with 1 mg/kg·d rhIGF-I/IGFBP-3 showed significant increases in both OCA and N-telopeptide compared with the changes in placebo-treated patients (P = 0.03 and P < 0.01, respectively) during the 8-wk infusion period. Similar (statistically not significant) trends were observed when analyzing serum levels of procollagen peptide and urinary excretion of desoxypyridinoline as markers of bone turnover (data not shown). No statistically significant differences were noted when evaluating differences in bone remodeling between groups at different time points (data not shown).
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, placebo patients and those treated with a lower dose of rhIGF-I/IGFBP-3 had lost 6.1% (P = 0.04) and 6.9% (P = 0.13) of hip BMD at 6 months after surgery, respectively. Patients treated for 8 wk with 1 mg/kg·d rhIGF-I/IGFBP-3, on the other hand, regained a portion of their femoral BMD after a significant initial loss of 5.5% (P values compared with baseline 0.01 and 0.05 at 4 and 8 wk, respectively) after hip fracture surgery. At 6 months after surgery, these women showed a small and statistically not significant decrease (-2.6%, P = 0.53) in hip BMD from baseline. There were no statistically significant differences in bone density between groups at different time points (data not shown).
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In patients treated with 1.0 mg/kg·d rhIGF-I/IGFBP-3, grip strength had increased from baseline by 11.4% (P = 0.04) by the end of the study, compared with losses of 0.8% (P = 0.97) and 11.6% (P = 0.16) in patients treated with 0.5 mg/kg·d rhIGF-I/IGFBP-3 or placebo, respectively (Fig. 4). At 6 months postfracture, 1 mg/kg·d-treated patients showed significantly more grip strength than those treated with placebo (P = 0.02). No statistically significant differences in strength were observed between both rhIGF-I/IGFBP groups or between 0.5 mg/kg·d and placebo (data not shown). The increase in muscle strength in the high-dose group was associated with a statistically significantly positive effect on the ability to arise from a seated position without assistance (P = 0.03 vs. placebo and 0.5 mg/kg·d-treated patients combined) (Fig. 5). The changes in functional ability in the 0.5 mg/kg·d group were not different from those in the placebo group and were pooled to increase the number of observations. No statistically significant differences were observed when comparing the 1.0 mg/kg·d and placebo groups alone.
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In this explorative pilot study in elderly osteoporotic women, we demonstrated the feasibility and safety of different doses of rhIGF-I delivered as a complex with its natural binding protein-3 (rhIGFBP-3) and administered as a continuous sc infusion using a controlled rate mini-pump. Both in terms of compliance and tolerance, our results are encouraging. Of the 33 women who were enrolled, 30 completed the study. Both doses of rhIGF-I/IGFBP-3 were well tolerated, and their safety profile was similar to that of placebo. There were no significant differences in the incidence of serious clinical effects or laboratory abnormalities between the three groups. None of the subjects on rhIGF-I/IGFBP-3 developed hypoglycemia or other drug-induced adverse events during the course of the study.
The broad range of biological activities of IGF-I and the availability of rhIGF-I have encouraged researchers to investigate various potential therapeutic uses, including the treatment of (male idiopathic) osteoporosis (14). Unfortunately, hypoglycemia, edema, intracranial hypertension and papiledema, syncopal reactions, arthralgia, fatigue, headache, and dyspnea have been observed in association with free rhIGF-I administration (15, 16, 17, 18, 19), limiting its therapeutic potential. In the study by Johansson et al. (14) in idiopathic osteoporosis, as many as 10 of 12 patients reported one or more side effects during rhIGF-I treatment, the most frequent being tachycardia, headache, dizziness, nausea, and swelling of the nasal mucosa. Although the precise biological mechanisms underlying these rhIGF-I side effects are not entirely understood, at least part of these (especially hypoglycemia and associated changes) seem related to the presence of supraphysiological levels of free IGF-I (15).
One approach to avoiding these acute side effects is to increase the pool of IGF-I that circulates within a complex with IGFBP-3. This can be accomplished through the administration of rhIGF-I bound in equimolar proportions to rhIGFBP-3 (rhIGF-I/IGFBP-3). IGFBP-3 is the main carrier of IGFs in the circulation and is considered to regulate the free, presumably active, IGF concentration (20). IGF complexes composed of IGF peptide, IGFBP-3, and an acid-labile subunit have, indeed, been shown to represent the vast majority of circulating endogenous IGF-I (21). Because unbound IGFBP-3 is not normally present in circulation, there is no significant capacity to bind and maintain exogenous free IGF-I in circulation. Administration of moderate doses of rhIGF-I, therefore, results in high concentrations of exogenous free IGF-I, and the initiation of a hypoglycemic response and related side effects. Administration of rhIGF-I/IGFBP-3, on the other hand, may take advantage of the naturally occurring excess acid-labile subunit present in circulation because the binding protein IGFBP-3 is no longer in limiting concentrations. Increasing the circulating pool of IGF-I in the ternary complex should, therefore, allow greater systemic exposure and provide a more physiological delivery of IGF-I to target tissues, and induce less side effects. In line with this assumption, preclinical pharmacology studies in rats showed that rhIGF-I/IGFBP-3 administered sc daily for 8 wk resulted in positive effects on muscle and bone tissues that were equal to or greater than those observed with equimolar doses of rhIGF-I alone for the same duration (22). Although a significant decrease in serum glucose occurred after injection of rhIGF-I alone, the positive effects of rhIGF-I/IGFBP-3 were attained without inducing hypoglycemia, supporting the concept that rhIGF-I/IGFBP-3 significantly reduces acute dose-limiting pharmacological adverse events. This concept is further supported by the present study, demonstrating that 1 mg/kg·d rhIGF-I/IGFBP-3 (delivering 200 µg/kg IGF-I) can be safely administered as a continuous sc infusion to elderly women for at least up to 8 consecutive weeks.
In metabolically normal humans, short-term sc administration of rhIGF-I increases biochemical estimates of bone turnover, even in old age (23, 24). In line with these studies, our findings indicate that treatment with rhIGF-I/IGFBP-3 at a dose of 1 mg/kg·d stimulates bone metabolism in frail osteoporotic patients. Both parameters of bone formation and resorption increased, however, and we are unable to derive from our biomarker data whether one of the processes increased to a greater degree. If, indeed, rhIGF-I would be capable of stimulating bone formation to a disproportionately greater degree than bone resorption, rhIGF-I could provide a means to stimulate clinically significant increases in bone mass. In our study, placebo-treated subjects had an average bone mineral loss at the contralateral hip of about 6% during the first 6 months after the injury, as expected (3). At 6 months postfracture (4 months after the 8-wk infusion), a similar statistically significant loss was observed in the low-dose (0.5 mg/kg·d) rhIGF-I/IGFBP-3 group, compared with a nonsignificant decline of only about 1.5% in patients treated with high-dose (1 mg/kg·d) rhIGF-I/IGFBP-3. These results suggest that femoral bone mass in the high-dose group was preserved despite an initial transient phase of decreasing density during therapy—presumably reflecting widening of the remodeling space—and are consistent with a subsequent increase in bone density following infusion. In line with this assumption, we previously observed an increase in bone mass following rhIGF-I/IGFBP-3 in the ovariectomized rat model, resulting in an improvement of mechanical competence (25).
Despite advances in surgical treatment and anesthesia, most hip fracture patients have residual disability and some can no longer lead an independent life. Only 40% of patients able to walk independently before proximal femoral fracture are able to do so 6 months after the event (2). Although the prognosis depends in part on functional status before the fracture, regaining strength and mobility is essential to functional recovery and longer-term patient health (26). In previous studies, muscle strength seemed to be the main determinant of various tests of functional ability after proximal femoral fracture (27). In our current trial, the increase in muscle strength (from baseline) in 1.0 mg/kg·d-treated patients was associated with a (potentially) positive effect on the ability to rise without assistance from the sitting position. Women treated with the higher dose of rhIGF-I/IGFBP-3 displayed approximately 20% greater grip strength than placebo or low-dose rhIGF-I/IGFBP-3-treated patients. About 80% of the elderly women treated with 1.0 mg/kg·d were able to raise themselves from an armless chair without assistance from equipment or human help at 3 and 6 months post surgery. By comparison, 3 months after surgery, 55% of the placebo and low-dose patients could rise without help from equipment or another person, and this improved to 60% by the end of the study.
The present investigation has important limitations, and the results should be interpreted in the context of its design. In particular, our experiment was primarily intended to be a Phase II clinical feasibility study and was not designed to demonstrate differences between groups. Although we observed several significant changes from baseline in the high-dose rhIGF-I/IGFBP-3 group, we acknowledge that the number of observations was small and the confidence limits correspondingly wide. For most variables, we were unable to document statistically significant differences between treatment groups. Moreover, it remains to be established if and to what extent, potentially positive effects of high-dose rhIGF-I/IGFBP-3 on bone density and muscle function would be clinically relevant (e.g. reduce the risk of fracture recurrence or improve functional outcome). In this regard, it should be emphasized that we only observed beneficial trends in the context of an underpowered pilot study and that larger Phase II and Phase III trials will be required to confirm our preliminary findings.
We conclude that a 2-month infusion of rhIGF-I/IGFBP-3 in elderly women with recent hip fracture is feasible, safe, and well tolerated. In addition, the results of our exploratory study suggest that rhIGF-I/IGFBP-3 could potentially increase bone density and enhance functional recovery following hip fracture. In the context of a small exploratory trial, these positive trends should be interpreted with caution, but they support the need for future trials to clarify the therapeutic utility of rhIGF-I/IGFBP-3 in elderly subjects with osteoporosis.
Acknowledgments
The expert data management by S. Breemans, V. Pousset, H. Leroi, A. Bogaers, and J. Mertens is gratefully acknowledged. We express our gratitude to the surgeons Drs. P. Cuyvers, C. Dierckx, R. Driessen, H. Lenskens, J. Oosterbosch, D. Oprins, T. Pittevils, L. Vanfleteren, D. Van Lommel, and R. Witvrouw.
Footnotes
This study was supported by a grant from Celtrix Pharmaceuticals, Inc. (San Jose, CA). A preliminary summary of the first results of this study was selected for oral presentation at the 1998 Joint Meeting of the International Bone and Mineral Society and the American Society for Bone and Mineral Research [Bone, 1998; 25(Suppl.): S157].
S.B. is a Senior Clinical Investigator of the Fund for Scientific Research–Flanders, Belgium (F.W.O.–Vlaanderen) and holder of the Leuven University Chair for Metabolic Bone Diseases, founded and supported by Merck Sharp & Dohme.
Abbreviations: BMD, Bone mineral density; IGFBP-3, IGF binding protein-3; OCA, osteocalcin; rhIGF, recombinant human IGF.
Received September 9, 2000.
Accepted January 7, 2002.
References
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