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Elderly Patients with Adult-Onset Growth Hormone Deficiency Are Not Osteopenic¹

Department of Endocrinology, Christie Hospital National Health Service Trust, Manchester, United Kingdom M20 4BX; the Department of Diagnostic Radiology, University of Manchester (J.E.A.), Manchester, United Kingdom M13 9PT; and the University Department of Geriatric Medicine, South Manchester University Hospital Trust (P.A.O.), Manchester, United Kingdom M20 8LR

Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester, United Kingdom M20 4BX.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The age-related decline in GH secretion has been implicated in the development of osteoporosis. GH-deficient adults show a significant reduction in bone mineral density (BMD), which is greater in those with childhood-onset GH deficiency than in those with GH deficiency occurring in adult life. To determine whether GH deficiency in late adult life causes a reduction in BMD beyond the decline observed with increasing age, we studied 21 patients over the age of 60 yr with GH deficiency caused by organic pituitary disease and 23 controls of similar age and sex distribution and BMI. Dual energy x-ray absorptiometry was used to determine total bone mass and BMD at the hip and in the lumbar spine. Serum osteocalcin was determined in all subjects and urinary deoxypyridinoline/creatinine ratio in 19 patients and 21 controls. The median (range) known duration of GH deficiency in the patients was 8 yr (range, 4–41 yr).

The median (range) total bone mass was 2774 g (range, 1534–3734) in the patients and 2717 g (range, 1235–3549) in the controls (P = 0.42). Specific measurements of BMD made at L2–L4, the right femoral neck, the right femoral trochanter, and Ward’s triangle were 1.234 (range, 0.778–1.507) vs. 1.144 g/cm² (range, 0.809–1.466; P = 0.48), 0.921 (range, 0.605–1.372) vs. 0.96 g/cm² (range, 0.534–1.315; P = 0.62), 0.92 (range, 0.523–1.229) vs. 0.915 g/cm² (range, 0.353–1.313; P = 0.68), and 0.773 (range, 0.408–1.289) vs. 0.806 g/cm² (range, 0.353–1.154; P = 0.81) in the patients and controls, respectively. The median (range) serum osteocalcin was 11.5 (range, 3.6–23.0) vs. 15.1 ng/mL (range, 0.7–40.5; P = 0.019) in the patients and controls, respectively. The median (range) deoxypyridinoline cross-links/creatinine ratio was 3.5 µmol/mol (range, 0.8–8.3) in the patients and 4.9 µmol/mol (range, 3.0–9.7) in the controls (P 0.038). There was a significant correlation between serum insulin-like growth factor I and total bone mass in the controls, but not in the patients.

These data demonstrate that BMD is not significantly altered in GH-deficient adults over the age of 60 yr. Markers of bone formation and resorption are decreased, however, suggesting that bone turnover is reduced. Further studies are required to determine whether the reduction in bone turnover in these patients is of benefit.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE DECLINE in bone mineral density (BMD) associated with advancing age is well recognized. Genetic, environmental, pathophysiological, pharmacological, and endocrinological factors may influence the rate of loss of bone mineral from the human skeleton (1, 2). GH secretion declines with increasing age by approximately 14%/decade of adult life (3), and the reduction in endogenous GH secretion has been suggested as a contributory factor in the age-related decline in BMD (4) and the pathogenesis of osteoporosis (5). Further support is given to this hypothesis by the finding that adults with normal hypothalamic-pituitary function who have osteoporosis have lower serum insulin-like growth factor I (IGF-I) concentrations than adults with normal BMD (6).

Adults with GH deficiency have a reduced BMD compared with healthy age- and sex-matched controls (7, 8, 9, 10, 11, 12, 13, 14, 15), placing them at an increased risk of sustaining fractures (16). Furthermore, adults who developed GH deficiency during childhood have a greater reduction in BMD than those who developed GH deficiency in adult life (9), suggesting that the age at which GH deficiency occurs may have some bearing on the degree of osteopenia that develops in these subjects. GH replacement therapy in adults results in an early rise in serum osteocalcin (17) and urinary deoxypyridinoline cross-links (18), indicating an increase in bone turnover. The increased bone turnover and remodeling associated with GH therapy result in a significant reduction in BMD after 6 months, followed by a return to baseline BMD values at 12 months (19). After 2 yr of GH therapy, BMD is significantly elevated compared with baseline measurements and may still be capable of a further increase if GH therapy is continued (20). The ability of GH replacement therapy to reverse the osteopenia associated with GH deficiency is a major indication for GH therapy in adults, aged between 20–60 yr, with hypothalamic pituitary disease (21).

We have previously demonstrated that despite the age-related decline in GH secretion, adults over 60 yr of age with hypothalamic-pituitary disease are GH deficient compared with control subjects (22). The degree of GH deficiency was sufficient to cause a reduction in serum IGF-I and changes in body composition in the patients compared with control values (23). To determine whether GH deficiency occurring in these subjects causes changes in bone turnover or a significant reduction in BMD beyond that observed with increasing age, we have studied markers of bone formation and resorption and BMD measured using dual energy x-ray absorptiometry.

	Subjects and Methods

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Patients and controls

Twenty-one patients (15 male) with hypothalamic-pituitary disease were studied, all of whom were over 60 yr of age (Table 1). The median (range) estimated duration of GH deficiency was 8 (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) yr; 1 patient had been GH deficient for less than 5 yr, 13 patients for 5–9 yr, 6 patients for 10–19 years, and 3 for over 20 yr. Two of the patients had isolated GH deficiency, and of the remaining 19 patients, all were gonadotropin deficient, 15 were ACTH deficient, and 12 were TSH deficient. Ten of the 14 men with gonadotropin deficiency were receiving testosterone replacement therapy. None of the women had ever received estrogen replacement therapy. All patients with ACTH deficiency were receiving replacement therapy with hydrocortisone (n = 12), prednisolone (n = 2), or cortisone acetate (n = 1), and those with TSH deficiency were receiving T₄. One patient had previously received GH replacement therapy, which he had taken for 6 months and had stopped it 1 yr before taking part in this study.

All the subjects in this study had previously undergone a 24-h GH profile. Fifteen of the patients had no evidence of spontaneous GH secretion during the 24-h profile (assay sensitivity, 0.4 µg/L), the remaining six patients demonstrated spontaneous GH secretion. All of the controls had demonstrable GH secretion on the 24-h profile.

The study was approved by the South Manchester Area Health Authority ethics committee. All subjects gave written informed consent before taking part in the study.

Measurement of bone mineral

Dual energy x-ray absorptiometry was used to determine the BMD of the lumber spine (L2–L4) and the right hip at three sites, the femoral neck, Ward’s triangle, and the trochanteric region, using a Lunar DPX-L scanner (Lunar Corp., Madison, WI). A total body scan was performed to assess total bone mass. Mean BMD was measured in grams per cm²; total bone mass was measured in grams. The precision (coefficient of variation) was 0.5% in the spine, 2.5% in the femoral neck, and 1.0% for total bone mass.

Serum IGF-I measurement

Blood was drawn at 0900 h after an overnight fast. Serum IGF-I was measured, after acid-alcohol extraction, by an in-house RIA. The samples were assayed in duplicate as a single batch. The reference preparation used was NIBSC 87/518. The intraassay coefficients of variation for mean IGF-I concentrations of 46, 246, and 706 ng/mL were 11.3%, 6.5%, and 4.7%, respectively. The sensitivity of this assay was 14 ng/mL.

Markers of bone turnover

Serum osteocalcin was measured at 0900 h after an overnight fast, using a two-site immunoradiometric assay (DSL, Webster, TX). All samples were assayed in a single batch. The sensitivity of this assay was 0.27 ng/mL. The intraassay variabilities were 4.6%, 2.9%, and 1.4% at 2.88, 9.84, and 28.2 ng/mL, respectively.

Urinary deoxypyridinoline cross-links were measured using a competitive enzyme immunoassay (Metra Biosystems, Mountainview, CA). Aliquots were taken from a 24-h urine collection. All samples were assayed in a single batch. The sensitivity of this assay was 1.1 nmol/L. The intraassay variabilities were 8.4%, 4.3%, and 5.5% for deoxypyridinoline cross-link concentrations of 10.7, 30, and 174.7 nmol/L, respectively. To correct for variations in urine concentrations, the results are expressed as a molar ratio between deoxypyridinoline cross-links and creatinine concentrations.

Statistics

Results are expressed as the median (with the range in parentheses). Comparisons between the patient and control groups were made using the Mann-Whitney U test. The Pearson correlation was used to determine relationships between parameters. P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the patient and control groups, the medians (ranges) were: for age, 66.0 (61.0–85.7) vs. 70.6 (60.8–87.5) yr; for height, 1.730 (1.486–1.842) vs. 1.690 (1.498–1.858) m; for weight, 85.5 (55.0–108.0) vs. 76.0 (45.0–101.5) kg; and for BMI, 27.8 (22.7–37.3) kg/m² vs. 25.9 (20.1–37.0) kg/m², respectively (not significantly different). Serum IGF-I was greater in the controls than in the patients [150 (65–255) ng/mL vs. 102 (14–162) ng/mL; P = 0.0001]. The median (range) known duration of GH deficiency in the patients was 8 (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41) yr (Table 1).

BMD

The median (range) total bone mass was 2774 (1534–3734) g in the patients and 2717 (1235–3549) g in the controls (P = 0.42). Specific measurements of BMD made at L2–L4, the right femoral neck, the right femoral trochanter, and Ward’s triangle were 1.234 g/cm² (0.778–1.507) vs. 1.144 g/cm² (0.809–1.466; P = 0.48), 0.921 g/cm² (0.605–1.372) vs. 0.96 g/cm² (0.534–1.315; P = 0.62), 0.92 g/cm² (0.523–1.229) vs. 0.915 g/cm² (0.353–1.313; P = 0.68), and 0.773 g/cm² (0.408–1.289) vs. 0.806 g/cm² (0.353–1.154; P = 0.81) in the patients and controls, respectively (Fig. 1). When these values were converted into age-specific SD scores, these findings were unchanged (Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 1. Total bone mass and BMD in the lumbar spine and at the hip in patients and controls. The median values are indicated by the bars.

The median (range) serum osteocalcin was 11.5 (3.6–23.0) vs. 15.1 (0.7–40.5) ng/mL (P = 0.019) in the patients and controls, respectively. Urinary deoxypyridinoline cross-links were measured in 19 of the patients and 21 of the controls. The median (range) deoxypyridinoline cross-links/creatinine ratio was 3.5 (0.8–8.3) µmol/mol in the patients and 4.9 (3.0–9.7) µmol/mol in the controls (P = 0.038). In the control group there was a significant correlation between serum osteocalcin and area under the curve for GH (r = 0.43; P = 0.039) and between urinary deoxypyridinoline cross-links and age (r = 0.64; P = 0.002). These relationships were not seen in the patient group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Studies of adults with GH deficiency have demonstrated that BMD is reduced compared with that in the normal population, placing them at an increased risk of fracture. These studies were performed on patients with childhood-onset GH deficiency (12, 13, 14, 15) or adult-onset GH deficiency (7, 8, 9) or in a mixed subject population (10, 11). Comparison of BMD results in adults with GH deficiency reveals a greater degree of osteopenia in the childhood-onset form (9). It appears, therefore, that the age of onset of GH deficiency is an important factor in determining the severity of the associated osteopenia. This may in part be related to the age at which bone mineralization is completed. The majority of bone mineral acquisition is complete early in the third decade of life (24, 25); however, some studies suggest that this process may continue, at a reduced rate, into the fourth decade (26, 27). Adults who develop GH deficiency after the age of 30 yr also develop osteopenia, but it is less severe with increasing age (9). In this study we have shown that adults over the age of 60 yr with adult-onset GH deficiency who are receiving appropriate replacement therapy for anterior pituitary hormone deficits, excluding GH, are not osteopenic compared with healthy subjects of similar age, sex, and BMI.

GH secretion declines with age by approximately 14% per decade of adult life (3). Some of the physical changes that occur with aging in healthy subjects, i.e. increased fat mass, reduced lean mass, and reduced bone mass, are similar to the changes seen in young adults with GH deficiency. These observations have led to the supposition that the decline in GH secretion may have a role in the physiological changes that occur as a result of increasing age (4, 28). The patients with organic pituitary disease in this study have been shown to be GH deficient compared with appropriate controls (22). Spontaneous GH secretion was markedly reduced, 16 subjects had no detectable GH secretion using a standard GH immunoradiometric assay, and there was a greatly reduced GH response to arginine stimulation (22). There was, however, an overlap of both spontaneous and stimulated GH secretion between the controls and a small number of the patients. This continuum in GH secretion is mirrored by a continuum in the biological end points of GH action. Thus, the biological manifestations of organic GH deficiency in the elderly are attenuated compared with those in younger adults with adult-onset GH deficiency. Evidence for this is provided by the more modest changes in body composition that occur in the elderly with organic GH deficiency; there is a significant increase in fat mass, but fat-free mass, which is reduced in young GH-deficient adults, does not appear to be affected by GH deficiency in the elderly (23). It is less surprising, therefore, that the elderly with organic GH deficiency are not osteopenic compared with their healthy peers.

The action of GH on bone appears to be mediated via the production of IGF-I by osteoblasts (29, 30, 31). The IGF-I content of bone declines with increasing age, which, it has been postulated, may reflect the age-related fall in GH secretion (32). Serum IGF-I correlates to BMD in younger patients with GH deficiency (10). We have demonstrated a correlation between IGF-I and total bone mass in the controls, but this relationship was not present in the patients, suggesting that GH is not a major determinant of bone mass in this age group. The role of GH in the production of IGF-I within bone in the elderly, therefore, may be a relatively minor one, as many other factors, including sex steroid concentrations, PTH, and cortisol levels, have been shown to influence IGF-I production.

Although this study demonstrates that elderly subjects with GH deficiency are not osteopenic, we have found that serum osteocalcin and urinary deoxypyridinoline cross-links are reduced, indicating that bone formation and resorption are reduced. Similar findings have been reported in GH-deficient children and young adults with childhood-onset GH deficiency (33). It would, therefore, seem that the primary effect of GH deficiency on bone is to reduce bone turnover, but the effect that this has on BMD is dictated by the patient’s age. Thus, GH deficiency in childhood or early adulthood, when bone mineral is being acquired, results in relatively severe osteopenia, but as the age of onset of GH deficiency increases, the extent of the osteopenia declines until the point is reached when BMD is not compromised. Indeed, a recent study by Garnero et al. suggests that subjects with reduced bone turnover may be at a reduced risk of developing osteoporosis (34). Organic GH deficiency in the elderly may, therefore, reduce the risk of osteoporotic fractures in this group of patients.

Adults who are GH deficient as the result of organic pituitary disease are likely to have additional anterior pituitary hormone deficits and be taking replacement therapy. Estrogen deficiency (35) and glucocorticoid therapy (36) are both potent causes of osteopenia. It is, therefore, possible that underreplacement of sex steroid deficiency or overreplacement with glucocorticosteroids contributes significantly to the severity of the osteopenia found in patients with organic pituitary disease. When patients with isolated GH deficiency are compared with patients with GH deficiency and gonadotropin deficiency, ACTH deficiency, or both, BMD is not significantly different, indicating that it is GH that causes the osteopenia observed in these patients (9, 15). In the current study, 19 of the 21 patients had gonadotropin deficiency. None of the women, patients or controls, was receiving estrogen replacement therapy as they were all well into the postmenopausal age range, and 4 of the men were not receiving sex steroid replacement despite having gonadotropin deficiency. Fifteen of the patients had ACTH deficiency and were receiving standard replacement therapy with hydrocortisone, cortisone acetate, or prednisolone. If this subgroup of patients is compared with the controls, their BMD was not significantly reduced, suggesting that glucocorticoid replacement therapy in conventional dosage in patients with ACTH deficiency per se does not appear to cause osteopenia. Corticosteroids exert their effects on bone by reducing bone formation, as evidenced by low serum levels of osteocalcin in the presence of increased bone resorption (36, 37). The patients in this study with ACTH deficiency were receiving a standard dose of steroid replacement therapy (30 mg hydrocortisone daily or equivalent). A recent study by Peacey et al. (38) demonstrated that a large proportion of patients with primary and secondary hypoadrenalism receiving standard glucocorticoid replacement therapy were being overtreated. A 30% reduction in the glucocorticoid dose caused a significant increase in serum osteocalcin. In our study the patients had significantly lower serum osteocalcin levels and urinary deoxypyridinoline/creatinine ratios compared with controls, a picture more typical of that seen in GH deficiency (39) than that due to glucocorticoid excess.

GH replacement therapy in adults has been shown to have a profound effect on bone remodeling, as evidenced by a rise in both serum osteocalcin (17, 19, 20, 40, 41) and urinary excretion of markers of bone resorption (18, 20, 41) early in treatment. Longer term treatment results in an increase in BMD (20). The correction of osteopenia is one of the major indications for GH replacement in adults with organic GH deficiency (21). We have shown that BMD is not reduced in adults over the age of 60 yr, although bone turnover appears to be reduced. Further studies are required to determine whether bone histomorphometry is abnormal in adults with GH deficiency over the age of 60 yr and whether, in contrast to younger GH-deficient adults (16), the fracture rate is not significantly different from that of the control population. At present, the absence of osteopenia in the elderly with GH deficiency weakens the case for GH replacement therapy in this age group.

	Acknowledgments

 
We are grateful to Jenny Jones, Department of Biochemistry, Institute of Child Health (London, UK), for performing the serum osteocalcin and urinary deoxypyridinoline cross-links assays. We also thank Prof. Mike Horan for access to the health status-defined panel to recruit the control subjects in this study.

	Footnotes

 
¹ This work was supported by Pharmacia-Upjohn and the North West Regional Health Authority Research Committee in purchasing the Lunar DPX-L.

Received October 23, 1996.

Revised January 15, 1997.

Accepted January 23, 1997.

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