Management of corticosteroid-induced osteoporosis.

OBJECTIVES: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS: This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS: Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. CONCLUSIONS: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.

Oestrogen and bone density: a comparison of tamoxifen and hypo-oestrogenaemia.

The effect of the anti-oestrogen tamoxifen on bone density in post-menopausal women with stage II breast cancer (n = 35) was compared with two untreated hypo-oestrogenaemic groups (premature ovarian failure, n = 20; prolactinoma, n = 19) and a group of women with prolactinomas and normal oestrogen levels (n = 12). Bone densities were normal in the euoestrogenaemic groups, but significantly reduced in both hypo-oestrogenaemic groups. Repeat measurements were available for 31 of the 35 tamoxifen-treated subjects after an interval of 33.9 +/- 14.7 months. The anti-oestrogen action of tamoxifen was not associated with accelerated bone loss of the spine or hip, an outcome that was clearly demonstrable in hypo-oestrogenaemic disorders.

Prolactin and the rat kidney: a clearance and micropuncture study.

PRL is a pituitary hormone with important osmoregulatory properties in lower vertebrates and has been reported to decrease renal water and electrolyte excretion in mammals. Although several studies have suggested that the proximal tubule is the major site of action of PRL, no direct examination of such an effect has been made. In the present study we used micropuncture and clearance techniques to examine the effect of ovine PRL (oPRL) infusion on single nephron and whole kidney function in anesthetized volume-expanded rats pretreated with bromocriptine to suppress endogenous PRL release. oPRL infusion was associated with a significant reduction in urinary sodium, potassium, and water excretion compared to changes seen in the control group. There was no significant effect of oPRL on whole kidney glomerular filtration rate, renal plasma flow, filtration fraction, renal blood flow, renal vascular resistance, or arterial pressure compared to those in control rats. Single nephron studies failed to detect any significant effect of oPRL on single nephron glomerular filtration rate and absolute or fractional reabsorption by the proximal convoluted tubule. Although arginine vasopressin was detected in the oPRL preparation, the quantity infused was negligible compared to the plasma levels found in anesthetized rats prepared for kidney micropuncture. Our results suggest that oPRL exerts a renal tubular action separate from arginine vasopressin to decrease water and electrolyte excretion which occurs beyond the last superficial convolution of the proximal convoluted tubule.

Correlation of Nb2 bioassay and radioimmunoassay values for human serum prolactin.

The availability of a sensitive and specific bioassay (BA) for PRL in human serum has made possible a comparative assessment of PRL bioactivity and immunoactivity in normal and abnormal serum specimens. Serum was studied from 20 normal subjects and 54 patients with a variety of disorders relating to PRL secretion. The correlation between the results of both assays was very close in all subjects. The mean BA/RIA ratio in normal subjects was 0.90, with a range from 0.67-1.33, and in patients with disordered PRL secretion the mean BA/RIA ratio was 0.94, with a range from 0.53-1.58. Similar results were obtained with PRL stimulatory testing using TRH, metoclopramide, and domperidone, and samples of culture medium from both PRL-secreting and non-PRL-secreting human pituitary tumor cultures. In one patient with a high proportion of "big, big" PRL and hyperprolactinaemia a BA/RIA ratio of 2.47 was found, a value well outside the normal range. However another patient with a similar history had a ratio of 0.82, in the range observed in normal subjects. These findings indicate that in a wide variety of clinical disorders the correlation between PRL bioactivity in the Nb2 system and immunoactivity in human serum samples is remarkably good under basal and stimulated conditions. One exception was found, but the nature of the underlying PRL abnormality in this patient remains to be investigated.

Effects of bromocriptine on single nephron and whole-kidney function in rats.

Bromocriptine (BRC) is a semisynthetic ergot alkaloid possessing dopamine agonistic activity. We had previously observed significant changes in renal hemodynamics in rats pretreated with BRC to suppress endogenous prolactin plasma levels. To investigate further the effects of BRC on single nephron and whole-kidney function, micropuncture and clearance experiments were performed on euvolemic and volume-expanded rats pretreated with BRC (1 mg i.p.) or solvent. Both groups of BRC-pretreated rats had a significantly higher renal plasma flow and a lower arterial pressure, filtration fraction and renal vascular resistance than control (solvent-treated) rats. In volume-expanded rats, BRC caused a small but significant decrease in whole-kidney glomerular filtration rate (GFR) and an increase in superficial single nephron GFR; BRC did not affect GFR or single nephron GFR in euvolemic rats. Proximal tubular reabsorption and urinary excretion of water and electrolytes were not altered by BRC under conditions of euvolemia or volume expansion. It was concluded that BRC exerts a dopamine agonist-like effect to increase renal plasma flow and suppress endogenous plasma prolactin levels, whereas the urinary water and electrolyte excretion and superficial proximal tubular reabsorption are not altered appreciably. The increased ratio of single nephron GFR/GFR suggests that in volume-expanded rats, BRC redistributes glomerular filtration to superficial nephrons, possible by preferential dilation of superficial afferent arterioles.

Prolactin status in chronic nephropathy in the rat.

Decreased specific prolactin binding to kidney membrane preparations, and an upward trend in serum prolactin levels were observed concomitantly with the onset of chronic progressive nephropathy im male rats of the OFA Sandoz SPF strain. Females of the same strain developed a less severe form of the disease at a later age, but failed to show the changes in prolactin status seen in male rats. Nephropathy in both male and female animals was associated with morphological abnormalities of a predominantly tubular nature, but was not associated with development of renal failure as indicated by serum urea and creatinine levels. Possible mechanisms for the observed alterations in prolactin status are discussed.

Prolactin status in experimentally induced acute renal failure in the rat.

Serum prolactin levels were elevated in male Sprague-Dawley rats with acute renal failure induced by glycerol administration. Specific prolactin binding to kidney membrane preparations was reduced in glycerol and antirat glomerular basement membrane serum-treated rats, after morphological and biochemical acute renal failure was evident. Extensive tubular damage after glycerol administration may account for loss of renal binding, since prolactin receptors are mainly tubular in localization. However, the predominant glomerulopathy, with less severe tubular lesions, after antirat glomerular basement membrane serum suggests that reduced renal prolactin binding in these animals is unlikely to be due to tubular destruction alone. Thus, alterations in prolactin status occur with development of experimentally induced acute renal failure and suggest altered renal responsiveness to prolactin in uraemia.

Prolactin receptors in the rat kidney.

Specific binding of 125I-labelled ovine prolactin iodinated by a lactoperoxidase method was demonstrated in crude membrane preparations of kidneys and adrenals of male Sprague-Dawley rats and livers from female rats. Membrane preparations derived from the 100,000 g fractions of tissue homogenates contained most of the specific prolactin binding. Kinetic and affinity characteristics of prolactin binding to kidney membranes were examined in detail. Maximal specific binding occurred after incubation for 30 h at room temperature. Scatchard analysis indicated that prolactin binding to kidney membranes was of high affinity (dissociation constant = 1.4 x 10(-10) mol/l) and similar to that for liver membranes, although kidney membranes from male rats bound approximately sixfold less prolactin/mg membrane protein than did liver membranes from female rats. Specific prolactin binding was demonstrated in both renal medulla and cortex. Autoradiography showed maximal prolactin binding activity in the epithelial cells of the proximal tubule and faint activity in the tubular cells throughout the nephron. Specificity of uptake by proximal tubular cells was indicated by the gross reduction in prolactin activity when excess ovine prolactin was administered simultaneously. The demonstration of specific binding sites for prolactin localized primarily in the proximal tubules was consistent with renal action of prolactin, predominantly on sodium metabolism.

Tests of prolactin secretion in diagnosis of prolactinomas.

Prolactin-secreting tumours of the pituitary were identified and treated by transsphenoidal microsurgery in fourteen infertile females with hyperprolactinaemia. Resting prolactin levels were 590--9000 mU/1 (mean 3400). In seven patients, tomography of the pituitary fossa was normal and resting prolactin levels were 590-6000 mU/1 (mean 3400). In these patients the pre-operative diagnosis prolactinoma in these patients was made by demonstrating loss of the normal circadian prolactin profile and impaired prolactin response to intravenous thyrotrophin-releasing hormone (T.R.H.) and metoclopramide stimulation. Prolactin response to the acute oral administration of L-dopa and bromocriptine was of less diagnostic value. Preoperative assessment of anterior pituitary function identified abnormalities other than hyperprolactinaemia in four patients (28%). Post-operative assessment indicated that microsurgery was curative in twelve patients (86%), selective in all, and without significant side-effect. It is concluded that dynamic tests such as T.R.H. and metoclopramide stimulation have considerable value in identifying hyperprolactinaemic patients with prolactin-secreting adenomas, particularly those which are radiologically occult.

Laboratory assessment of prolactin status.

The laboratory assessment of prolactin status was evaluated by detailed study of 921 subjects (587 normal subjects and 334 patients with pathological conditions). The effect on serum prolactin levels of age, sex, circadian rhythm, pulsatility of secretion, stress, drug ingestion, and pregnancy was defined in normal subjects. The normal prolactin responses to stimulation (TRH metoclopramide) and suppression (L-dopa, bromocriptine) were also determined. Basal prolactin levels were measured in patients with defined pathological conditions including prolactinoma, idiopathic hyperprolactinaemia, acromegaly, Cushing's disease, chronic renal failure, primary hypothyroidism, pituitary ablation, Kallman's syndrome, Nelson's syndrome, growth hormone deficiency, gonadotrophin deficiency, craniopharyngioma, panhypopituitarism, and chronic progressive arthropathy. Based on these data, a strategy for the routine laboratory assessment of prolactin status is outlined.

Hyperprolactinaemia in renal disease.

Basal prolactin concentrations in 357 patients with renal disease of defined pathology have been compared with those in 210 control subjects. Elevated prolactin concentrations were found in 113 renal patients (32%) including 53 patients in whom elevated concentrations were possibly attributable to drug therapy. In the remaining 60 patients who had hyperprolactinaemia not attributable to drugs, elevated concentrations (P less than 0.005) were found exclusively in patients with impaired renal function. A significant correlation was observed between prolactin and creatinine concentrations in these patients (r = 0.45 P less than 0.005) and prolactin reverted towards normal after successful renal transplantation. A significant arteriovenous prolactin concentration difference across the kidney (mean 16% range 8-29% P less than 0.02) was found in seven patients with non-renal non-endocrine disease. It is concluded that the hyperprolactinaemia found commonly in patients with impaired renal function is only partly attributable to drug therapy. The positive correlation between prolactin and creatinine reversion of prolactin towards normal after successful transplantation and arteriovenous hormone concentration differences across the normal kidney suggests that the kidney has a important role in prolactin metabolism. Abnormal regulation of prolactin secretion in renal failure may also be involved.

Bone scan findings in hypervitaminosis D: case report.

Bone scans in three patients showed generalized symmetrical increased uptake of radiopharmaceutical by the skeleton and absent or faint kidney images. It is thought that these appearances may be attributable to excess vitamin D, but other possible contributing factors, including the presence of renal osteodystrophy, are discussed.

The forgotten nodule: complications of sacral nodules in rheumatoid arthritis.

Nodules commonly occur in rheumatoid arthritis and occasionally give rise to complications. The sacral nodule is easily missed and may ulcerate to produce extensive sacral sores which may lead to serious and even fatal complications in patients with rheumatoid arthritis. Seven cases are reported which illustrate some of these features.