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Original Studies |
Departments of Medicine (E.S.K., F.C., E.S., R.L., J.P.B.), Pathology (D.D.), and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, N.Y. 10032; St. Joseph Hospital (C.J.R.), Bangor Maine; Regional Bone Center (F.C., R.L., D.D.), Helen Hayes Hospital, West Haverstraw, New York; Irving Center for Clinical Research (D.M.), Columbia-Presbyterian Medical Center, New York, N.Y. 10032; Queen Elizabeth Hospital (F.C.), Hong Kong
Address correspondence and requests for reprints to: John P. Bilezikian, M.D., Department of Medicine, College of Physicians and Surgeons, 630 W. 168th Street, New York, N.Y. 10032.
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Abstract |
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Histomorphometric analysis of bone biopsy specimens showed significant reductions in cancellous bone volume (31%; P < 0.001), cortical width (28%; P < 0.05), osteoid surface (33%; P < 0.01), and bone formation rate (54%; P < 0.01) when results were compared with age-matched control subjects. Percent eroded surface was normal and was correlated inversely with serum IGF-I levels (r = -0.5; P < 0.04).
These results suggest that serum IGF-I levels are reduced in men with idiopathic osteoporosis and that IGF-I correlates with and may contribute to the reduction in lumbar spine bone mass density (BMD). The low IGF-I levels may reflect the reduction in bone formation demonstrated by histomorphometry. Insights into the etiology of idiopathic osteoporosis in men may be revealed by further studies of the IGF-I axis.
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Introduction |
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With no readily identifiable causes of reduced bone density in men with idiopathic osteoporosis, it is attractive to consider the possibility that this disorder is the result of fundamental abnormalities of bone cell function or of the hormonal or paracrine pathways that regulate bone cell metabolism. In this regard, insulin-like growth factor I (IGF-I) is a prominent candidate (7). IGF-I has been shown to be important in the differentiation, maturation, and recruitment of osteoblasts (8, 9). It is produced locally in skeletal tissue where it constitutes a major extravascular depot (10). The skeleton is second only to the liver as a source of circulating levels of IGF-I (11). Some studies have shown reduced serum levels of IGF-I in patients with idiopathic osteoporosis (6, 12).
Idiopathic osteoporosis thus affords the opportunity to apply current concepts in bone cell biology along with bone densitometry, bone histomorphometry, and calciotropic hormones to the evaluation of affected individuals. We have studied 24 middle-aged men with idiopathic osteoporosis. Use of selective inclusion and exclusion criteria maximized the aim to focus on a relatively homogeneous group of study subjects. The subsequent discovery of potential pathophysiological abnormalities common to most of these individuals suggests that at least one form of idiopathic osteoporosis in men may have a unifying mechanism.
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Subjects and Methods |
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A total of 24 men were enrolled, 18 at Columbia-Presbyterian Medical Center (CPMC) and 6 at Helen Hayes Hospital (HHH). Inclusion criteria for this study were a Z score of less than -2.0 or a T-score of less than -2.5 at the lumbar spine or femoral neck. Twenty-three patients met both Z-score and T-score criteria. One patient (age 62) was included by T-score criteria only at both the lumbar spine and femoral neck. All subjects were under 70 yr of age and had normal gonadal, hepatic, and adrenal function. No patient had a history of hyperthyroidism, glucocorticoid or anticonvulsant use, diabetes mellitus, gastrointestinal disease, gastrointestinal surgery, malignancy, or any known metabolic bone disease. No patient had a history of alcoholism, although alcohol use not exceeding the equivalent of 2 ounces of spirits daily was permitted.
A complete history and physical examination was performed at the time of enrollment. Physical activity was assessed with a detailed questionnaire that addressed activity from daily routine, occupation, and any formal exercise program. Dietary calcium intake was assessed with a 3-day prospective diary. During the average period of observation (15 months), all patients were instructed to achieve a total daily calcium intake of 1500 mg. In most cases, calcium supplementation was required to meet this goal. Patients were also instructed to take 400 IU Vitamin D.
Serum and urine measurements
Serum concentrations of total calcium, phosphorus, alkaline
phosphatase activity, albumin, blood urea nitrogen (BUN), and
creatinine were measured by automated techniques (Technicon
Instruments, Tarrytown, NY). Parathyroid hormone concentration was
determined by an immunoradiometric assay for intact parathyroid hormone
(13). 25-Hydroxyvitamin D concentration was measured by
radioimmunoassay (RIA) (14), and 1,25 dihydroxyvitamin D concentration
was measured by radioreceptor assay (15). Thyroid stimulating hormone
(TSH) was measured using a highly sensitive microparticle enzyme
immunoassay (16). Total testosterone concentration was measured by RIA
(17). Urinary free cortisol was determined by a well-established
protocol employing an initial extraction step followed by RIA (18).
Normal ranges for these assays are given in Table 1
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Bone mineral density
Bone mineral density (BMD) of the lumbar spine, right femoral neck, and nondominant forearm was measured by dual energy x-ray absorptiometer (DXA) using a QDR-1000 bone densitometer (Hologic, Waltham MA) at CPMC and the QDR-1500 bone densitometer at HHH. Machines were cross-calibrated ten times using the European spine phantom (26). Means were calculated for each vertebra representing low density, medium density, and high density. A regression curve was fitted yielding the following equation: BMDCPMC = -0.023 + 1.046 X BMDHHH.
Adjusting for the difference in calibration between the two machines had no impact on our findings. At CPMC, the in vitro reproducibility of the QDR-1000 is 0.28%, and at HHH, 0.51%. The short-term in vivo coefficient of variation at CPMC in a group of postmenopausal osteoporotic women is 1.2% at the lumbar spine and 1.4% at the femoral neck; at HHH 0.8% at the lumbar spine and 1.5% at the femoral neck. Bone density was expressed as grams per cm2, and as T and Z scores, which compare by standard deviation individual bone density determinations to those of a younger and age-matched, normal population of the same gender, respectively.
Bone biopsy
Percutaneous transiliac crest bone biopsies were performed on 18 patients before implementing the treatment protocol. Four patients who had previously received therapy for osteoporosis (i.e. bisphosphonates, calcitonin, or fluoride) were biopsied 6 months after discontinuing therapy. When bone biopsy results of these 4 men, previously on medication for osteoporosis, were compared with the 14 men never on medication, there was no statistically significant difference in the findings. The bone biopsy specimen was obtained according to well-established technique (27) after earlier labeling with 2 time-spaced doses of tetracycline. Tissue processing, staining, and sectioning were performed according to standard procedures (28). All histomorphometric indices were designated in accordance with the nomenclature recommended by the American Society for Bone and Mineral Research (29). Reference values for bone biopsy parameters were taken from published values for normal men (30, 31, 32, 33, 34).
Statistical analysis
All data, except for histomorphometry results, are expressed as the mean ± SEM. Bone biopsy data are expressed as the mean ± SD. Z scores for IGF-I were developed from laboratory reference ranges by decade of age (see methods of IGF-I). Simple regression models were used to assess the reliability of estimate and rate of change between two biochemical indices, and Student’s unpaired t test was used to assess the reliability that the distribution of observed IGF-I Z scores differed significantly from a mean of zero. For one specific aspect of this study, the evaluation of a relationship between IGF-I or osteocalcin and bone density, data accumulated over a 15 month period of observation were utilized. Multiple regression analysis using sequential sums of squares models with partial correlation coefficients estimated the unique proportion of variance in bone density trend accounted for by temporal changes in either IGF-I or osteocalcin after the confounding influence of age had been partialled from both the bone density and hormone measures. No adjustments for multiple comparison inflation of Type I error rates were made, and all results were tested at the 5% level.
This study was conducted with the approval of the Institutional Review Boards of Columbia Presbyterian Medical Center and Helen Hayes Hospital. All subjects gave written informed consent.
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Results |
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The mean age of the men in this group at the time of enrollment was 50.5 ± 1.9 yr (range 29–67). The majority of subjects (17/24 or 71%) came to medical attention because of fracture, usually of the vertebral spine (13/17); 3 patients sustained stress fractures of the lower extremities, and 1 had a traumatic hip fracture. The remaining 7 patients (29%) presented with back pain. Subsequent evaluation with thoracic or lumbar spine films was negative for fracture but revealed osteopenia. Osteoporosis was confirmed by DXA according to criteria of the World Health Organization (WHO) (35).
The majority of patients (58%) consumed alcohol rarely. Those who did report alcohol intake had a maximum of two drinks per day. One patient was a current smoker, and 38% had a past history of cigarette smoking with an average of 20 pack-years. None of the patients was sedentary; 21% of the group were engaged in a formal, daily exercise program, while an additional 50% led a very active lifestyle.
The average daily intake of calcium in this group, previously counseled by other physicians about osteoporosis, was 1408 ± 187 mg. Four patients with daily calcium intakes below 1000 mg were supplemented to achieve an intake of 1500 mg a day.
Eight patients (33%) had been treated with various therapies for osteoporosis including etidronate (5 men), calcitonin (4 men), and fluoride (2 men) for an average duration of 13.5 months (6–24 months). Mean time off all medication was 12 months before enrollment (3–36 months).
Bone densitometry
Mean lumbar spine BMD was 0.727 ± 0.02 g/cm2;
mean femoral neck 0.646 ± 0.02 g/cm2; mean radius at
the distal 1/3 site was 0.704 ± 0.01 g/cm2. Mean T
scores at the lumbar spine, femoral neck, and distal radius were
-3.5 ± 0.16, -3.03 ± 0.15, and -2.12 ± 0.26
respectively (Fig. 1); mean Z scores at
these three sites were -3.14 ± 0.17, -1.83 ± 0.15, and
-1.59 ± 0.25, respectively. While it is clear that cancellous
bone is most markedly involved in this group, as documented by
reductions in lumbar spine BMD (P < 0.05 as compared
with the femoral neck and radius), there is also substantial
involvement of the femoral neck, a site composed of a more even mixture
of cancellous and cortical elements (P < 0.05 as
compared with 1/3 site of radius BMD). Additionally, cortical bone, as
measured at the distal 1/3 site of the radius was not spared; 38% of
the patients were osteoporotic at this site, 38% had osteopenia, and
only 24% had normal bone density at the radius.
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Standard serum and urinary biochemical determinations are shown in
Table 1
. Mean serum concentrations of
calcium, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D
were all within the normal range. Although the mean PTH concentration
was also within normal limits, it was at the lower range of normal, and
five patients (21%) had PTH values no more than 15 pg/mL. Thyroid
function and urinary free cortisol excretion were within normal limits.
Testosterone was measured in several different laboratories, but in all
cases, values were within normal limits. Markers of bone formation and
bone resorption were in the normal range (Table 2) with the exception of a single patient
with elevated bone-specific alkaline phosphatase and an
N-telopeptide value at the upper limit of normal. In general,
N-telopeptide correlated well with all markers of bone formation
measured; BSAP (r = +0.68; P < 0.005),
osteocalcin (r = + 0.55; P < 0.02), and PICP
(r = + 0.46; P < 0.05) though pyridinoline only
showed a trend with PICP (r = +0.43; P < 0.07).
The mean 24-h urinary calcium excretion was normal, although one
patient with a daily calcium intake of 2900 mg had slightly elevated
excretion of 338 mg/g creatinine.
Insulin-like growth factor-I
The mean IGF-I concentration was reduced compared with that of a
control group of 24 normal, nonosteoporotic men, 157 ± 8.6 ng/mL
vs. 197 ± 14 ng/mL(P < 0.04). IGF-I
declined with age (r = -0.49; P < 0.02;
Fig. 2), but the observed reduction in IGF-I levels was
greater than expected for age-related changes. These reduced values are
best seen by plotting specific data points against age-expected
means ± 1 SD (Fig. 2). Fifteen patients have values
that are approximately 1 SD below the age-related mean, and
one patient is almost 2 SD below age-expected means.
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). The vast majority of patients, 21,
were found to have Z scores below the normal mean. Univariate analysis
of IGF-I Z scores reveals that, when tested against the hypothesis that
a mean Z score for any group should be equal to zero, this shift to the
left in the average Z score to -0.75 is highly significant
(P = 0.0002). For the 24 nonosteoporotic men, the mean
Z score was -0.18. This value was not significantly different from an
expected mean Z score of zero (P = 0.52).
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The contribution of IGF-I to the variance of BMD at all three sites was
evaluated over a mean follow-up of 15 months. Multiple regression
analysis of paired points, with age held constant, revealed that IGF-I
contributed 15% to the variance in the change in lumbar spine density.
It did not contribute significantly to the variance in bone density at
either the femoral neck or distal 1/3 radius (Table 3). In contrast, levels of osteocalcin
did not show a significant correlation with either lumbar spine or
femoral neck BMD (Table 3). Osteocalcin correlated significantly with
bone density at the distal 1/3 radius. Including PTH in the regression
models did not affect the results.
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Results from the bone biopsies were compared with data for
age-matched normal men from the literature (Table 4). Bone volume was reduced by 31%
(P < 0.001), cortical width by 28% (P
< 0.05), osteoid surface by 33% (P < 0.01), and bone
formation rate by 54% (P < 0.01). Mineralizing
surface was also markedly reduced. When bone biopsy parameters were
analyzed for correlations with IGF-I and IGFBP3, there was an inverse
relationship between percent eroded surface and IGF-I (r = -0.5;
P < 0.04, Fig. 4) and
between IGFBP3 and eroded surface(r = -0.45; P =.06).
No other significant relationships were noted between IGF-I, IGFBP3,
and the other bone biopsy parameters.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The routine evaluation of these men did not give specific clues as to potential underlying etiologies of osteoporosis. In this respect, our study is similar to the published experience (1, 5). However, evaluation of IGF-I and IGFBP3 levels in these men alone and in relation to PTH, bone mass measurement, and histomorphometry has provided noteworthy insights. The significance of the reduced IGF-I levels is substantiated by the fact that the likelihood of a similarly-sized group of unselected men, having similar reductions in IGF-I levels is 1 in 5000 (univariate hypothesis that the true mean Z score = 0; P = 0.0002). The significant contribution of IGF-I to the variance in lumbar spine BMD lends clinical support to the hypothesis that IGF-I plays an important role in this form of osteoporosis. Further physiologic evidence is provided by the histomorphometric finding that the more reduced the IGF-I level the greater the percent eroded bone surface. This relationship is particularly intriguing as IGF-I is believed to contribute to the actions of osteoblasts to refill resorption cavities (37). If lower IGF-I levels reflect an impairment in this osteoblast process, greater eroded surface might be expected.
IGF-I is known to decline in both serum and bone with aging (9, 38). This age-related reduction in IGF-I is mirrored by the known decline in bone mass with aging, and investigators have long sought to link these two processes. Bennett et al.(39) demonstrated a significant decline in both IGF-I and BMD in aging postmenopausal osteoporotic women, but no correlation between BMD and IGF-I was appreciated when age was held constant. In contrast, Ljunghall et al.(12) demonstrated in a group of 12 middle-aged men with idiopathic osteoporosis a significant reduction in IGF-I values compared with age-matched normals and a significant correlation between IGF-I and bone density of the spine and forearm. Similarly, Reed et al. (6) described reduced values of IGF-I in a group of 30 young men and women with idiopathic osteoporosis and a significant correlation between IGF-I and osteoblastic surface. However, an age-related decline in IGF-I and a relationship between IGF-I and bone density could not be established.
Our histomorphometric finding of decreased bone formation and decreased osteoid surface in men with idiopathic osteoporosis suggests an abnormality in osteoblast function and corroborates previous work (6). De Vernejoul et al. (2) and Khosla et al. (40) each demonstrated in men with idiopathic osteoporosis that, in addition to reductions in trabecular volume and cortical thickness, there was a reduction in mean wall thickness, which is the amount of bone deposited by the osteoblast in each remodeling unit. Jackson et al. (41) demonstrated significantly reduced osteoblastic surface in idiopathic osteoporotic men as compared with hypogonadal men and postmenopausal women. The extent to which these abnormalities are reflective of a fundamental abnormality of the osteoblast itself or of its responsiveness to agonists like IGF-I is not known.
PTH could potentially be responsible for reductions in IGF-I and abnormal osteoblast activity. The anabolic effect of PTH on osteoblasts is mediated in vitro by IGF-I (42). PTH also stimulates production of IGFBP3 in bone cells (43). Wong et al. (44) have shown that osteoblasts isolated from patients with idiopathic osteoporosis have a significantly decreased cyclic AMP (cAMP) response to PTH when compared with osteoblasts derived from young normals. Because cAMP is a major cell signaling system for PTH (45, 46), the reduction in IGF-I levels could be the result of abnormal osteoblast responsiveness to PTH. In addition to this possibility, our results suggest that inadequate PTH itself could contribute to reduced IGF-I. The average PTH concentration in our group of men was 25 pg/mL, an unusually low mean value for this age. Five patients had levels at the lower limits of normal, a distinctly unusual finding considering the expected age-related increase in PTH concentrations (47). Although we cannot rule out the effects of dietary calcium, it is unlikely that the nutritional amount of calcium all men received, 1500 mg, affected PTH levels. These observations are of particular interest in view of the work of Silverberg et al. (48), which showed that in postmenopausal women with osteoporosis, the parathyroid hormone response to a mild hypocalcemic stimulus is well below that of nonosteoporotic age-matched control subjects. It is not yet known whether blunted PTH responsiveness could be a mechanism for abnormal PTH function in men with idiopathic osteoporosis. Although the precise abnormality in the relationship between PTH and IGF-I/IGFBP3 has not been elucidated by this study, the trend towards a significant relationship between PTH and IGFBP3 suggests that this question bears further investigation.
The growth hormone (GH) axis must also be considered as an explanation for the relatively low IGF-I levels in this group of men with unexplained osteoporosis. GH deficiency is associated with reduced bone density (49) and patients with GH deficiency have reduced values of IGF-I (50). Several points argue against a mechanistic role for GH deficiency in this process. First, one would have to postulate isolated GH deficiency because our patients had otherwise normal anterior pituitary function. Spontaneous isolated GH deficiency in adults is unusual (51). Second, Ljunghall et al. (12) tested GH secretion in some of their patients with idiopathic osteoporosis and found the GH axis to be normal. Third, in ongoing studies related to this investigation, provocative GH testing appears to be normal (52).
Finally, the gonadal axis is important to consider in a group of middle-aged men with reduced bone density. Free testosterone declines with age (53), although total testosterone can remain fairly normal until age 55. IGF-I has been shown to correlate directly with free testosterone and inversely with sex hormone binding globulin (SHBG), which increases with age (53, 54). However, it is unlikely that gonadal dysfunction was abnormal in this group of men, because total testosterone was normal and there were no symptoms or signs of hypogonadism. In addition, IGF-I levels are interpreted with regard to age, a relationship for IGF-I that takes into account the age-related decline in gonadal function. Reduced IGF-I concentration in these men is thus beyond what one would expect simply as a matter of age-related declines in androgen levels. A further note is that the histomorphometric findings by bone biopsy are quite different from those reported in bone biopsies obtained from hypogonadal men (41).
Our findings lend further support to the hypothesis that the syndrome of idiopathic osteoporosis in men, when it presents clinically, can best be explained by osteoblastic dysfunction and reduced bone formation. The important interrelationships between IGF-I, the IGF binding proteins, PTH, and systemic and local growth factors have yet to be more fully understood. Future studies of the IGF-I axis will be valuable both to clarify some of the complex mechanisms described above and to assist in the development of appropriate treatment strategies for men with this disorder.
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Acknowledgments |
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Footnotes |
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Received January 7, 1997.
Revised May 22, 1997.
Accepted June 9, 1997.
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References |
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