Faculty Bibliography

The effect of chronic administration of growth hormone (GH) to osteoporotic patients was studied using the techniques of total body neutron activation analysis, whole body counting, calcium tracer kinetics, photon absorptiometry, quantitative microradiography, and urinary hydroxyproline. Two dosage schedules were utilized for six months each: 2 units daily and 0.2 w3/4 units of GH daily (where W represents body weight expressed in kg). The lower dosage (2 units) did not produce any appreciable change in the indices studied. Following the higher dose, no evidence of any anabolic effect was apparent in most patients (i.e., no increase in total body levels of Ca, Na, K, P, or Cl). Increases were noted in the urinary calcium excretion rate and in the urinary hydroxyproline excretion. Bone mineral content decreased. The bone biopsies displayed an increase in bone formation and resorption surfaces in response to treatment, but these changes were not statistically significant. It may be concluded that under the conditions of this study, GH administration did not result in an increment in skeletal mass. Several side effects that are characteristic of acromegaly were observed, including hyperglycemia, hypertension, arthralgia, and the carpal tunnel syndrome. Because of the lack of demonstrated benefit and the associated complications of therapy, GH administration does not appear to be of value in the treatment of osteoporosis.

The change in body composition in acromegaly that resulted from pituitary irradiation was examined using the technic of total body neutron activation analysis. Before treatment, increased ratios of total body P:Ca, P:K and Na:K were noted. After pituitary irradiation, the total body levels of P, Na and K were reduced in a proportion that indicated restoration of body composition towards normal. Skeletal mass (total body calcium) decreased into the range observed in osteoporosis in several patients. Trabecular bone mass, as reflected by the Singh Index, was consistently reduced, and two patients had vertebral compression fractures. Local bone mass as determined by photon absorptiometry was reduced when the values were normalized for age, sex and body size. It is postulated that in untreated acromegaly there is differential bone remodelling with an increase in cortical bone accompanied by a reduced trabecular bone mass. When reduction of hGH levels is accomplished with treatment, cortical apposition may decrease. Since the increased cortical bone mass probably aids in preventing vertebral compression fractures, the treated acromegalic patient may incur an increased risk of fractures. This risk may be increased further by the hypogonadism which may arise secondary to pituitary irradiation or surgery. It would be prudent to ensure that the hypogonadal acromegalic patient receives an adequate calcium intake and sex hormone replacement therapy.

Total-body levels of calcium and phosphorus (reflecting skeletal mass) and total-body levels of potassium (reflecting muscle mass) were measured by neutron activation analysis in 39 men and 40 women ages 30-90 yr. In order to intercompare the total body calcium (TBCa) values in a heterogeneous population, such as this, it was necessary to normalize the data for skeletal size. The normalization consisted of dividing the absolute calcium level by the predicted calcium level for each individual matched to a set of critical parameters. The parameter used in the computation of normal values were age, sex, muscle mass, i.e., total body potassium (TBK) and height. For the calcium data of the women, it was necessary to add an age correction factor after the age of 55 yr. The calcium ratio(mean ratio of the predicted to measured TBCa) in men was 1.000 +/- 7.8% and in women 0.996 +/- 7.1%. The TBCa of normal males and females can thus be predicted to +/- 13% (at the 90% confidence level). An exception to this was found in males (70-90 yr) who exhibited a mean calcium ratio greater than 1.13. The derivative of TBCa with time was determined for this population of men and women by taking into account the dependency of calcium on three time dependent variables, height, TBK, and an explicit age correction factor in the case of the women. The mean rate of loss of TBCa in women was 0.37% and 1.1% per year before and after menopause (50 yr). In the males, the average rate of loss of TBCa was 0.7% per year after 50 yr of age. The pattern of total body phosphorus (TBP) loss with age paralleled that of TBCa as the ratio of TBP/TBCa was rather constant with age. The constancy of the ratio suggests that the mineral composition of bone does not change significantly with age. The rate of loss of TBK with age was also related directly to that of TBCa. The mean ratio of TBK/TBCa was 9.9 in females and 8.0 in males and this ratio remained relatively constant from 30-70 yr. Thus, the mechanism responsible for the loss of bone with age, whether nutritional deficiency or decreased gonadal function and physical activity may also be responsible for the loss of muscle mass with age.

Five patients with osteoporosis were treated with human growth hormone (hGH) for a year and the changes in their skin were studied by light and electron microscopy. The abnormally thin skin of osteoporosis appeared to change towards normal after treatment with hGH. There was a consistent proliferation of blood vessels, and increased number of mast cells and fibrocytes. The collagen bundles and elastic tissue fibers appeared hyperplastic and more horizontally oriented. The fine, vertical elastic fibrils of the papillary dermis had appeared decreased before treatment, but seemed to be restored to their normal configuration after treatment. Since there was no evidence of stimulation of hair, sebum, or melanin such as occurs in acromegaly, it is suggested that the scope of the direct action of hGH on the skin is limited to mesenchymal structures.

Human growth hormone (hGH) was administered to a group of osteoporotic patients at two dosage levels for a period of 6 mo each. The first dose employed was 2 units subcutaneously daily, and the second dose was 0.2W-3/4 units (where W is body weight expressed in kg) daily. There was no significant change in serum-cholesterol or triglyceride concentration despite the production of hyperglycemia and soft-tissue swelling on the higher dosage regimen. A number of factors may account for the conflict between our findings and a previous report in which hGH administration had a lypocholesterolemic, hyperglyceridemic effect. These factors include differences in sex, age, dosage, and duration of treatment. Nonetheless, it is clear that from a therapeutic vantage, even if hGH were readily available, it would not be a useful hypocholesterolemic agent.

Thirty-six osteoporotic patients who underwent several therapeutic regimes were studied on two occasions by photon absorptiometry and total-body neutron activation analysis (TBNAA). These determinations were made at a mean interval of 8.9 plus or minus 0.8 months. The 8-cm radial site was chosen for the photon absorptiometry which was performed with the Norland-Instruments Densitometer. Mean initial bone mineral content (BMC) was 0.724 plus or minus 0.069 gm/cm and mean bone width was 1.235 plus or minus 0.072 cm. The mean percent change in BMC (%deltaBMC) was 1.02 plus or minus 4.2. The initial total-body calcium (TBCa) as determined by TBNAA was reduced when compared with values that would be expected from empirically derived formulas. The mean percent change in TB-Ca (%deltaTB-Ca) was -3.2 plus or minus 4.7. Most patients displayed a change in BMC and TB-Ca that was at least 2 s.d. greater than the precision of the methods used (%deltaTB-Ca greater than 2). No relationship was found between the deltaBMC and the deltaTB-Ca (r = 0.17). These findings suggest that changes in the radical BMC at the 8-cm site cannot be extrapolated to indicate changes in skeletal mass in response to treatment of osteoporosis. Whether photon absorptiometry at other sites or at multiple sites provides a closer relationship to changes in skeletal mass (TB-Ba) remains to be determined.

A group of ten acromegalic patients, who had no history of heart failure, was studied to determine whether subtle carciac impairment may also be common. None had clinical evidence of coronary artery disease or severe hypertension. Systolic time intervals were recorded in each patient and compared with normal values predicted for sex and heart rate by our own controls and published data. The results indicate that measurable abnormalities in left ventricular performance are common in this sampling. Known duration and activity of disease (growth hormone levels at time of study) did not correlate with the time intervals. The results are consistent with cardiomyopathic effect of excessive growth hormone.