We have previously described the histomorphometric and biochemical indices of bone in a 43-year-old woman with the Werner syndrome and severe osteoporosis [4]. This patient was shown to have a low circulating concentration of insulin-like growth factor 1 (IGF-1). Diminished IGF-1 synthesis may contribute to osteoblastic suppression and bone loss because IGF-1 stimulates bone formation by increasing osteoblastic activity [5, 6]. The impairment with age in the growth hormone-insulin-like growth factor axis and resulting decrease in circulating IGF-1 levels have been implicated in the age-related decrease in lean body mass and bone mass [7]. However, an exact causal relation between reduced serum IGF-1 levels and osteoporosis has not been established [8]. Because examination of bone biopsy specimens showed that our patient had reduced osteoblastic activity in addition to low serum IGF-1 levels, we felt she would be an ideal candidate in whom to assess both the safety of recombinant human IGF-1 (rhIGF-1) and its effect on bone metabolism. We report the results of 6 months of daily subcutaneous doses of rhIGF-1.

Case Report

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Our patient's clinical presentation has been previously described and shows the typical history and physical findings of patients with the Werner syndrome [4]. Although menopause occurred when the patient was 31 years old, she began receiving conjugated estrogens and progesterone a few months after her last menstrual period and continued to receive them up to and throughout the study. Initial evaluation at our institution excluded secondary causes of osteoporosis. Skeletal radiographs showed marked radiolucency and compression fractures of almost all thoracic and lumbar vertebrae. Bone mineral densities (measured by QDR-2000; Hologic, Waltham, Massachusetts) of the L2 to L4 vertebrae, femoral neck, and radial shaft were 2.38, 3.93, and 2.0 standard deviations lower than the means for age-matched normal women, respectively.

A transcortical iliac crest bone biopsy was done after tetracycline labeling [9]. The histomorphometric data were consistent with a suppressed bone formation rate in light of the normal bone resorption rate [4].

Methods

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The Institutional Review Board of the University of Texas Southwestern Medical Center reviewed and approved the study protocol, and the patient gave informed consent for participation in the study. The patient underwent four study phases, each lasting 4 days in the inpatient setting of the general clinical research center. The control phase took place before rhIGF-1 treatment was initiated. The patient continued to receive routine medications, including calcium citrate (200 mg of elemental Ca twice a day) and estradiol transdermal system (0.05 mg twice a week). She was kept on a constant metabolic diet consisting of 800 mg of calcium, 800 mg of phosphorus, and 100 mEq of sodium. On days 1 to 3, urine was collected in three consecutive 24-hour pools for urinary calcium, phosphorus, sodium, hydroxyproline, creatinine, and pyridinoline cross-links. We obtained fasting venous blood samples on days 1 through 4 to measure routine chemistries and intact parathyroid hormone, osteocalcin, type I procollagen C-peptide, and IGF-1 levels [10]; on day 1, we obtained a blood sample to measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels [11]. We determined intestinal fractional calcium absorption using fecal recovery of orally administered Calcium-47 [12]. Because diurnal variations have been reported with serum procollagen levels [13], we obtained venous blood samples every 4 hours for 24 hours on day 2 to determine diurnal levels of serum type I procollagen C-peptide.

We determined bone mineral densities of the L2 to L4 vertebrae and the femoral neck using quantitative digital radiography (Hologic QDR 2000) and the bone density of the distal one third of the radius using a Norland single-photon absorptiometer (Madison, Wisconsin). Standing anterior-posterior and lateral radiographs of the thoracic and lumbar spine were also done.

After we completed the baseline evaluation (control phase), the patient was treated with rhIGF-1. (Genentech [South San Francisco, California] provided rhIGF-1 [IND#39397] free of charge but gave no other support.) The drug was administered subcutaneously starting at 30 µg/kg of body weight per day. At this dose, serum IGF-1 levels increased from low to normal levels that were age- and sex-matched (Figure 1). At 6 weeks, the dose was increased at increments of 15 µg/kg per day to 45 µg/kg per day, at 8 weeks to 60 µg/kg per day, and at 10 weeks to 75 µg/kg per day. Although no side effects were found at the latter dose, the serum IGF-1 level was abnormally high at 1000 ng/mL; the dose was therefore reduced to 60 µg/kg per day for weeks 19 to 26.

View larger version (79K): [in this window] [in a new window]   Figure 1. Serum insulin-like growth factor type 1 (IGF-1) and IGF-1-binding protein-3 (IGF-1-BP-3) levels before and during treatment with recombinant human IGF-1. \#9679; =serum IGF-1 levels measured at baseline and during inpatient and outpatient evaluations throughout the study period. = serum IGF-1-BP-3 levels measured at baseline and at various times during the first 20 weeks of therapy (normal range, 2.28 to 5.25 mg/L). The height of the dotted area under the curve shows varying rhIGF-1 dosing at different points during the 26-week study and allows comparisons of dose, serum IGF-1 levels, and IGF-1-BP levels. All samples (except those from baseline evaluation) were taken immediately before the single daily administration of rhIGF-1.

The patient was readmitted to the general clinical research center after 1 month, 3 months, and 6 months of treatment. Evaluations identical to those of the control phase were done. In addition to receiving inpatient evaluations, the patient was seen as an outpatient weekly during the first 6 weeks of therapy and every 2 weeks thereafter to monitor for side effects.

Results

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Symptoms

The patient tolerated the administration of rhIGF-1 with no identifiable side effects. Body weight remained stable during treatment with rhIGF-1. We found no evidence of increased intracranial pressure such as papilledema or hypoglycemic symptoms. She reported having less discomfort in her feet and "an improved sense of well-being."

Serum Insulin-like Growth Factor-1 and Insulin-like Growth Factor-Binding Protein-3 Concentration

As described previously, a single daily subcutaneous dose of rhIGF-1 (30 µg/kg per day) could increase circulating IGF-1 levels from low to normal (Figure 1). Doses greater than 30 µg/kg per day resulted in proportionally higher levels of circulating IGF-1. Random measurements showed that the serum IGF-binding protein-3 level remained normal during therapy.

Markers and Measures of Bone Metabolism

Serum calcium, phosphorus, and alkaline phosphatase levels did not change from baseline (Table 1). Serum osteocalcin and type I procollagen C-peptide increased at 1 month and remained elevated throughout therapy. Diurnal changes in serum type I procollagen C-peptide showed that values at 3 and 6 months of treatment were greater than those at baseline (data not shown). The mean serum type I procollagen C-peptide concentrations over 24 hours while the patient received rhIGF-1 therapy were statistically significantly higher than the baseline values.

Twenty-four-hour urinary calcium, hydroxyproline, and pyridinoline levels were higher after treatment with rhIGF-1 than before treatment (Table 1). The urinary pyridinoline level was lower at 6 months than at 3 months but remained elevated over the baseline value during all treatment phases.

Bone Density and Intestinal Calcium Absorption

During 6 months of treatment, the bone mineral density of the L2 to L4 vertebrae increased 3% (Table 1). However, the bone mineral densities of the femoral neck and radial shaft did not change. No new spinal fractures were shown on radiographs done during the study. Intestinal calcium absorption was in the low normal range (normal, 40% to 60%) [14] at baseline and was the same after 6 months of rhIGF-1 treatment. Absorption was approximately 12% higher during the first and third months of treatment. No significant changes were noted in serum values for 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone levels.

Other Tests

Other biochemical measurements before and during therapy with rhIGF-1 are listed in Table 1. Fasting serum glucose, cholesterol, and triglyceride levels did not change. We found no disturbances in serum electrolytes, liver enzymes, or measures of renal function.

Discussion

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The administration of rhIGF-1 increased several biochemical markers of bone turnover. Serum type 1 procollagen C-peptide and osteocalcin levels, both markers of bone formation, increased, although total serum alkaline phosphatase levels did not change. Urinary pyridinoline cross-links and hydroxyproline, both measures of bone resorption, increased with rhIGF-1 therapy compared with baseline values. Moreover, 24-hour urinary calcium levels increased in the absence of increased intestinal calcium absorption or serum 1,25-dihydroxyvitamin D, suggesting that bone was the source of increased urinary calcium.

Two reports of 1 week of treatment with rhIGF-1 have described increased bone turnover in normal postmenopausal women and in a man with idiopathic osteoporosis [14, 15]. In our patient being treated with transdermal estrogen, exogenous IGF-1 overcame the antiresorptive action of estrogen.

Despite the short duration of treatment, bone mineral density at the lumbar spine increased in excess of the coefficient of variation (2%) of the instrument used. Because bone mass measured at the femoral neck and radial shaft did not change compared with baseline values, the apparent gain in bone mass in the spine was probably not caused by bone redistribution but rather by increased bone formation in excess of resorption.

A single daily dose of rhIGF-1 administered subcutaneously at a dosage of 30 to 75 µg/kg per day was sufficient to increase the circulating IGF-1 level to normal and greater-than-normal levels. The dose dependence of IGF-1 action was suggested because 24-hour urinary calcium and serum type I procollagen C-peptide levels during treatment with 60 µg/kg of rhIGF-1 were higher than levels at lower doses.

The singular nature of this case makes its clinical relevance to other patients uncertain. However, sufficient evidence indicates that our patient's osteoporosis stemmed from a state of low bone formation. Decreased osteoblastic activity is important in age-related bone loss, and IGF-1 promotes bone formation. Our results may therefore be more relevant than those in normal or poorly defined osteoporotic patients. Lastly, we acknowledge that our observation of increased bone mass is based solely on bone density measurements. Therapy with rhIGF-1 may have stimulated bone turnover without a net increase in bone mass. Larger studies and bone histomorphometric analyses are necessary to adequately assess the safety and efficacy of rhIGF-1 in patients with osteoporosis and low bone-turnover states.