Sodium fluoride therapy of postmenopausal osteoporosis.

More than 30 yr of research has clearly established sodium fluoride as the most potent agent currently available for increasing spinal bone mass. The increase is dose-dependent and linear with time for at least 6 yr, probably as long as 10 yr. This is in keeping with observed pharmacological actions of fluoride to enhance recruitment of osteoblasts and matrix deposition without any consistent effect on bone resorption. Unfortunately this has not translated into therapeutic efficacy in terms of preventing the VFR in patients who are already fractured at the initiation of therapy. Whether fluoride will be effective in preventing the first fracture is currently being investigated. If successful in this regard it will not only be extremely useful as prophylaxis against osteoporotic vertebral fractures, but will also provide substantial insight into the pathogenesis of these fractures and the management of patients seen after the first or subsequent fracture. We predict that fluoride will turn out to be extremely useful for prophylaxis. Whether or not lower doses or intermittent fluoride therapy will prove to be effective in patients who have already sustained fractures, is also being actively investigated in controlled clinical trials. Given the difficulty in demonstrating therapeutic efficacy over the past 30 yr, with favorable outcomes only reported from uncontrolled studies, we are not as optimistic about these investigations. Side-effects of NaF are becoming more clearly understood and easier to manage. The gastrointestinal symptoms are short-lived and dependent on the dose and formulation. These symptoms infrequently prohibit the use of the drug. The painful lower extremity syndrome appears to us to represent a 'positive' response to NaF, reflecting abundant formation of new bone that is poorly mineralized. If detected on the basis of symptoms, therapy should be interrupted for 6-8 weeks, then restarted at a lower dose. This syndrome, while clearly related to NaF, appears to be idiosyncratic and not dose or formulation dependent. The data relating NaF to hip fractures cannot be completely ignored because of the major community health problem posed by hip fractures. However, the data are largely anecdotal. Putting all this together, we feel that there may be an important role for NaF in osteoporosis treatment but, for now, its use should be restricted to properly conducted controlled clinical trials.

Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss.

We devised a new method for examining the structural changes that occur in trabecular bone in aging and in osteoporosis. With simultaneous measurement of total perimeter and bone area in thin sections, indirect indices of mean trabecular plate thickness (MTPT) and mean trabecular plate density (MTPD) can be derived, such that trabecular bone volume = MTPD X MTPT. MTPD is an index of the probability that a scanning or test line will intersect a structural element of bone, and is the reciprocal of the mean distance between the midpoints of structural elements, multiplied by pi/2. We applied this method to iliac bone samples from 78 normal subjects, 100 patients with vertebral fracture, and 50 patients with hip fracture. The reduction in trabecular bone volume observed in normal subjects with increasing age was mainly due to a reduction in plate density, with no significant decrease in plate thickness. The further reduction in trabecular bone volume observed in patients with osteoporotic vertebral fracture was mainly due to a further reduction in plate density. There was a relatively smaller reduction in plate thickness that was statistically significant in males but not in females. Only in patients with hip fracture did trabecular thinning contribute substantially to the additional loss of trabecular bone in osteoporosis relative to age. These data indicate that age-related bone loss occurs principally by a process that removes entire structural elements of bone; those that remain are more widely separated and some may undergo compensatory thickening, but most slowly become reduced in thickness. We propose that the process of removal is initiated by increased depth of osteoclastic resorption cavities which leads to focal perforation of trabecular plates; this is followed by progressive enlargement of the perforations with conversion of plates to rods. The resulting structural changes are more severe in osteoporotic patients than in normal subjects, but have been completed in most patients before they develop symptoms.

Irreversible bone loss in osteomalacia. Comparison of radial photon absorptiometry with iliac bone histomorphometry during treatment.

We examined the relationships between the changes in bone mineral deficit in the radius, determined by single-energy photon absorptiometry at standard proximal and distal sites, and in the ilium, determined by bone histomorphometry, during the treatment of osteomalacia of diverse etiology in 28 patients. In the ilium, relative osteoid volume decreased by 75-80% in both cortical bone (from 6.0% to 1.5%) and trabecular bone (from 30.1% to 6.6%) during a mean treatment duration of 2 yr. There was also a significant fall in iliac cortical porosity from 10.3% to 7.8%. As a result, mineralized bone volume increased by 7.5% in cortical and by 40.1% in trabecular bone; the cortical and trabecular increments were correlated (r = 0.69, P less than 0.001). The properly weighted increase for the entire tissue sample was 18.6%. By contrast, there was no change in bone mineral at either radial site, although there was a 2% increase at both sites when allowance was made for age-related bone loss during treatment. The proximal and distal age-adjusted increments was correlated (r = 0.76, P less than 0.001), but there was no correlation between the changes in any photon absorptiometric and any histomorphometric index. In that iliac cortical bone turnover in normal subjects was 7.2%/yr, we estimated the rate of bone turnover to be less than 2%/yr at both proximal and distal radial sites, including any trabecular bone present at the distal site. Compared to appropriate control subjects, the bone mineral deficits fell during treatment from 19.2% to 17.1% at the proximal radius (greater than 95% cortical bone) and from 20.5% to 18.5% at the distal radius (greater than 75% cortical bone). In the ilium the deficits, assuming attainment of normal values for osteoid volume and cortical porosity, fell from 41.7% to 36.1% in cortical and from 31.5% to 6.3% in trabecular bone, the properly weighted combined deficit falling from 38.6% to 27.7%. The irreversible iliac cortical deficit was entirely due to cortical thinning because of increased net endosteal resorption; the resultant expansion of the marrow cavity offset the modest loss of fractional trabecular mineralized bone. We conclude: in osteomalacia there is a large irreversible and a small reversible bone mineral deficit at both proximal and distal radial sites, in similar proportion to the iliac cortex but of smaller magnitude; the anatomic basis of the irreversible bone mineral deficit at all three sites that persists despite correction of the mineralization defect by appropriate treatment is thinning of cortical bone, most likely owing to prolonged secondary hyperparathyroidism; (c) there is no evidence that the proportion of trabecular bone in the distal radius at any site proximal to the radioulnar joint has any relevance to the interpretation of measurements made at that site; (d) there are at least three functional subdivisions of trabecular bone depending on proximity to hematopoietic marrow, fatty marrow, or synovium; and (e) single photon absorptiometry of the radius is an excellent method for measuring cortical bone mass in the appendicular skeleton, but is of little value for the assessment of changes in trabecular bone status.

Agonist activity of the 3-hydroxy metabolites of tibolone through the oestrogen receptor in the mouse N20.1 oligodendrocyte cell line and normal human astrocytes.

17beta-oestradiol (E(2)) may have a beneficial impact on the development of age-related diseases, in part through alpha and beta oestrogen receptors (ER) in glia. Tibolone, a synthetic steroid, could influence glial-mediated neuroprotection if agonist oestrogenic activity is demonstrable. We used the N20.1 mouse oligodendrocyte cell line as a glial cell model to evaluate the response of ERalpha and ERbeta through oestrogen-response element (ERE) and AP-1-driven reporters to E(2), 4-hydroxytamoxifen (4OHT) and to two tibolone metabolites, 3alpha-hydroxytibolone (3alpha-OH-Tib) and 3beta-hydroxytibolone (3beta-OH-Tib). In addition, we tested the activity of these same ligands through the endogenous ERalpha in human normal astrocytes. Because endogenous ER was not detected in the N20.1 cells, we tested the ability of exogenous ER to activate transcription in response to ligands (100 nM) using a transient cotransfection assay with an ERalpha expression vector. To test the antagonist activity of 3alpha-OH-Tib and 3beta-OH-Tib, we used them in combination with E(2) (10(-8) M), at concentrations of 10(-7) M and 10(-6) M. The human normal astrocytes were treated similarly, with the exception that no ER-encoding DNA was used. Specific ER ligand mediated activity was shown using the E(2) antagonist ICI 182 780 and the pSG5 empty vector. E(2), 3alpha-OH-Tib, and 3beta-OH-Tib stimulated ERalpha on an ERE-promoter at each concentration (P < 0.001) but not at an AP-1-driven promoter. 4OHT was an effective antagonist, but did not exhibit agonist activity on the ERE-driven promoter. 4OHT was an effective agonist through ERalpha on an AP-1-driven promoter. 3alpha-OH-Tib and 3beta-OH-Tib were not effective antagonists of E(2). Both metabolites acted through the ER because the addition of an E(2) antagonist blocked their activity. These results show that 3alpha-OH-Tib and 3beta-OH-Tib exert agonist activity, yet lack antagonist or additive activity, through the ERalpha and ERbeta on an ERE-driven but not on an AP-1-driven promoter in a glial cell model and in normal human astrocytes. This contrasts with the effects of 4OHT, which exerted little or no agonist activity, but reduced E(2)-stimulated activity through ERalpha on the ERE, in the same cells.

Borderline-low serum thyrotropin level is correlated with increased fasting urinary hydroxyproline excretion.

BACKGROUND: Recent studies suggest that even mildly supraphysiologic thyroid hormonal status accelerates bone loss. In hyperthyroidism, increased bone resorption is the predominant mechanism for bone loss. We postulated that the changes in thyroid hormone status as reflected by low-normal and minimally subnormal serum thyrotropin level would have an effect on bone turnover and could be detected by a simple, noninvasive marker of bone resorption, fasting urinary total hydroxyproline-creatinine excretion (THP/Cr). METHODS: We retrospectively identified ambulatory patients with a restricted range of diagnoses who had had measurements of thyrotropin and THP/Cr performed within +/- 21 days. RESULTS: Of the 86 patients, 47 had thyrotropin levels greater than 1.0 mU/L. In these patients, no correlation was evident for thyrotropin and THP/Cr. Of the other 39 patients, 11 had suppressed thyrotropin levels (less than 0.1 mU/L) and showed clearly elevated values for THP/Cr, as expected from previous studies of hyperthyroidism. For 28 patients with thyrotropin in the borderline and low-normal range of 0.1 to 1.0 mU/L, a significant negative correlation with THP/Cr was found. The THP/Cr was positively correlated with serum alkaline phosphatase level, as expected with increased bone turnover. CONCLUSIONS: These results add further support to the hypothesis that even a minimal excess of thyroid hormones increases bone turnover and may contribute to accelerated bone loss.

Oral contraceptive use may protect against low bone mass. Henry Ford Hospital Osteoporosis Cooperative Research Group.

This cross-sectional retrospective epidemiologic study investigated risk factors for low bone mineral density (BMD) in a group of 2297 women, 76% of whom were postmenopausal. Reproductive information, history of oral contraceptive use, BMD measurements, and other data were available from women presenting to 12 osteoporosis screening centers in 1986 and 1987. Each woman was classified into a BMD category based on the range of BMD measurements at her respective center. Menopause, increasing age and years since menopause, and decreasing body mass index were associated with low BMD. A history of oral contraceptive use was protective against low BMD (odds ratio = 0.35, 95% confidence interval = 0.23 to 0.53). Multivariate analyses confirmed this result and further demonstrated that increasing duration of use was protective. These data suggest that prior use of oral contraceptive agents is associated with higher levels of BMD and that the degree of protection from lower BMD is related to duration of exposure.

Hyperparathyroidism following head and neck irradiation.

A history of head and neck irradiation in childhood or adolescence was found in 22 of 130 patients with primary hyperparathyroidism compared with only 12 of 400 control patients, a significant difference (P less than .025). Among 200 patients with a known history of childhood irradiation, biochemical or surgical evidence of hyperparathyroidism was found in ten, a prevalence of 5%. This is at least 30 times the prevalence of hyperparathyroidism in the general population (P less than .025). The data indicate that head and neck irradiation should be regarded as an important risk factor in the subsequent development of hyperparathyroidism.

Asymptomatic primary hyperparathyroidism discovered by multichannel biochemical screening: clinical course and considerations bearing on the need for surgical intervention.

The sustained effects of biochemical screening to increase both apparent incidence and age at diagnosis indicate that, without screening, most patients with primary hyperparathyroidism would would never be diagnosed. This suggests that asymptomatic patients discovered as a result of screening have a nonprogressive form of the disease, with adverse health effects that are few or nontraditional, for which treatment policies validated only in symptomatic patients may be inappropriate. Accordingly, in 1975 we formulated criteria for withholding surgical treatment from such patients. Of 174 who were eligible for study over a 10 year period, clinical, biochemical, and densitometric assessment was repeated after at least 1 year (mean 52 months) in 106 patients who did not differ in any initial characteristic from 68 patients in whom follow-up was inadequate. There was no change in symptoms, no disease complications, and no change in any index of hormone secretion or disease severity. In 30 patients, individual regression slopes against time were not significant for any serum measurement. In these patients the disease appeared to have stopped progressing by the time the diagnosis was made, most likely because of cessation of tumor growth. There was a significant deficit in appendicular cortical bone at the time of diagnosis but no further acceleration of bone loss thereafter. In an earlier study, surgical cure was followed by a modest increase in forearm bone density for the first 6 months, but even after 3 years only about 20% of the deficit was corrected. The deficit in bone density is smaller in the spine than in the forearm and is not accompanied by any increase in vertebral fracture risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of vertebral deformities in osteoporosis: measurement error or "rebound"?

Digitized morphometry of vertebral bodies on lateral spine films is used to identify and quantify vertebral deformities or fractures. One problem associated with this method is the phenomenon of "disappearing fractures," which results from the apparent increase in vertebral body heights of previously deformed vertebrae on subsequent radiographs. These have been considered biologically implausible and therefore a result of measurement error. Measurement error is unlikely to be unidirectional, so that a proportion of fractures identified by morphometry is also the result of measurement error. Since some vertebral deformities are real events, some disappearances of deformities detected by morphometry may be real events. In this report, we examine the data from our clinical trial of sodium fluoride in spinal osteoporosis to assess critically the plausibility of two hypotheses: (1) The "rebound" phenomenon results from measurement error. If this is the case, then some fractures of the same magnitude as the rebound must also represent measurement error. (2) Some deformed vertebrae in fact rebound toward their original shape and size, displaying an elastic response to deformation. If this occurs, then some vertebral deformities are transient events, not true fractures. We conclude that the variability inherent in morphometric data obtained from serial spine x-rays results in both disappearing fractures and a high false positive fracture rate. The use of more stringent criteria for defining significant deformities, or true fractures, will minimize these problems. We cannot exclude the second hypothesis, that some vertebral deformities may be transient events, but this needs further study.

Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis.

We measured indices of bone volume (cancellous and cortical) and bone surface (cancellous, endocortical, and intracortical) in intact, full-thickness transiliac bone biopsies obtained from 47 healthy white women (23 premenopausal and 24 postmenopausal) and 82 patients with postmenopausal osteoporosis. In the normal subjects there was the expected loss of cancellous bone with age, best shown by a reduction in bone surface/tissue volume, but no fall in cortical thickness with age despite a significant reduction in forearm bone density measured by single-photon absorptiometry. Bone surface/bone volume was about four times higher in cancellous than in cortical bone, and cancellous bone contributed about one-third of the total bone volume and about two-thirds of the bone surface when related to the core volume referent. In the osteoporotic patients, core width, an index of iliac bone thickness at the biopsy site, was reduced by 10%, but we could not determine whether this was the result of compaction of the core or of bone slenderness. All indices of bone volume, cortical as well as cancellous, were significantly smaller, as were the values for forearm bone densitometry; the relative deficits at different sites depended on whether they were expressed as percentages or as zeta scores. Bone surface/bone volume was increased in both cancellous and cortical bone, but bone surface/tissue volume was reduced in cancellous bone and increased in cortical bone. The proportions of total bone volume and surface contributed by cancellous and cortical bone were almost the same as in normal postmenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)

The direct examination of three-dimensional bone architecture in vitro by computed tomography.

We describe a new method for the direct examination of three-dimensional bone structure in vitro based on high-resolution computed tomography (CT). Unlike clinical CT, a three-dimensional reconstruction array is created directly, rather than a series of two-dimensional slices. All structural indices commonly determined from two-dimensional histologic sections can be obtained nondestructively from a large number of slices in each of three orthogonal directions. This permits a comprehensive description of structural variation within a specimen and greatly facilitates the study of structural anisotropy. A measure of three-dimensional connectivity (Euler number/tissue volume) has been determined for the first time in human cancellous bone and shown to correlate with several two-dimensional histomorphometric indices. The method has the potential for overcoming many of the limitations of current approaches to the study of bone architecture at the microscopic level.

Comparison of radiographic absorptiometry with dual-energy x-ray absorptiometry and quantitative computed tomography in normal older white and black women.

Bone mineral density (BMD) of the phalanges of the hand was measured by the technique of radiographic absorptiometry (RA) in 199 older postmenopausal women previously determined to have normal BMD by dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). The average age of the women was 66.8 +/- 4.9 years, and they were 19.9 +/- 6.7 years postmenopause. In the 54 black women, phalangeal BMD was 11.7% greater than in the 145 white women, a difference comparable to that found using DXA at the radial midshaft, the lumbar spine, and femoral neck. A correlation matrix comparing BMD measured by RA to BMD measured by DXA and QCT indicates that, in general, RA was related to the various DXA and QCT measurement sites as well as these sites were related to each other. When results for RA, DXA, and QCT obtained in our cohort of older women were compared to available reference data for peak adult bone mass, the average difference (SD units) from peak value was greatest for RA (-1.77 radius, -1.24 spine, -2.13 femoral neck, -2.34 QCT spine, and -2.71 phalanges). We conclude that RA is an acceptable measure of phalangeal BMD and that the data in our cohort can serve as reference data for older white and black women aged 55-75 years. Once the ability of RA to predict future fracture occurrence has been demonstrated, it could be rapidly deployed as a low-cost, widely available bone mass measurement technique.

Incidence of hip fractures in osteoporotic women treated with sodium fluoride.

It has been suggested recently that, although fluoride therapy may decrease the occurrence of vertebral fractures, it could increase the risk of hip fractures. To evaluate this possibility, we combined retrospective data from five medical centers that have had a large experience with this therapeutic regimen. In 416 osteoporotic patients who were followed for more than 1,000 patient-years of fluoride treatment, there were 17 nontraumatic hip fractures. This incidence of 1.6% per year is similar to the incidence, 1.9% per year, for 120 of the patients in this series who had been followed prospectively for 3 years prior to initiation of fluoride therapy. The expected incidence for women of the same age in the general community is 0.5% per year. Thus, untreated osteoporotic women are at increased risk for hip fracture, but treatment with fluoride seems neither to decrease nor to increase the incidence of hip fracture substantially.

Development and validation of a discriminative quality of life questionnaire for osteoporosis (the OPTQoL).

We report the development and validation of an osteoporosis-targeted quality of life questionnaire to measure the impact of the disease in the general population. From multiple focus groups with women with osteoporosis, healthy women at risk for osteoporosis, spouses and relatives of women with osteoporosis, and health care providers, we identified over 300 potential items related to the disease. A lengthy questionnaire incorporated these items and was administered to a second large study cohort of 222 women with clinical osteoporosis (history of fracture, significant height loss, and/or kyphosis); 101 women with known low bone mineral density levels that would categorize them as osteoporotic but who had not yet shown obvious physical manifestations of the disease; and 142 women with other conditions (such as arthritis, cancer, depression) expected to also have an impact on quality of life. Final items from among the original 300 were chosen for their demonstrated relationship with osteoporosis as measured by clinical manifestations and low bone density and with quality of life measured by a standard generic questionnaire, the SF-36. The final questionnaire contains 26 scored items in three domains-physical activity, adaptations, and fears- and six nonscored questions relating to osteoporotic changes and diagnosis. This instrument is unique among osteoporosis-targeted questionnaires in that it attempts to measure the total impact of the disease on quality of life within a population at a single point in time.

Measurement of vertebral area on spine x-rays in osteoporosis: reliability of digitizing techniques.

Much of the clinical research in osteoporosis is directed toward documenting a reduction in vertebral fracture rate, but there is considerable disagreement about defining and quantifying vertebral fractures. We have evaluated the technique of digitizing landmarks identified on lateral radiographs of thoracic and lumbar vertebrae and computing vertebral body area. Reduction in area indicates that fractures occurred. Radiographs from 10 patients with osteoporosis and vertebral fractures were obtained from each of two centers. Henry Ford Hospital (HFH) and Mayo Clinic (MC), and vertebral area for each individual in the complete set of 20 radiographs was calculated at each center. Measurements at the two centers differed by a multiplicative constant related to the method of recording landmarks on the radiographs that was estimated using 300 x-rays from HFH. After adjusting the MC areas for this multiplicative relationship, the average ratio of the HFH areas to the transformed MC areas of individual vertebrae (T4-L5) ranged from 0.98 to 1.06. The correlation between HFH and transformed MC areas for individual vertebrae averaged 0.85, with slopes between 0.87 and 1.00, intercept average -0.57. Within-patient rank correlation averaged 0.97. We conclude that radiographic digitization is a reliable and reproducible method of determining vertebral body dimensions that is suitable for evaluating radiographs obtained at different clinical sites and for comparison with normal data. This technique should prove useful for documenting the presence of a vertebral fracture that may not be readily apparent on visual inspection of radiographs and for monitoring serial changes in vertebral body dimensions in long-term epidemiologic and therapeutic studies.

Reference data for bone mass, calciotropic hormones, and biochemical markers of bone remodeling in older (55-75) postmenopausal white and black women.

From a random sample of our institution's health maintenance organization (HMO), we recruited 250 white women and 112 black women, aged 55-75, all of whom were 10 or more years postmenospause with minimal estrogen exposure and free of osteoporosis, other metabolic bone disease, and medical, surgical, or therapeutic situations that may influence bone loss. Bone mass was measured in the radius, spine, and femur by DXA and in L1 by QCT. Serum samples were analyzed for parathyroid hormone, calcidiol, calcitriol, osteocalcin, and bone alkaline phosphatase and urine samples analyzed for creatinine, calcium, and hydroxyproline. Mean Z score, based on published reference data for forearm and femoral neck BMD in the white women, was not significantly different from zero, but mean Z score at the lumbar spine was 0.6 (p < 0.001), 17.2% of the individual values being > 2.0. In normal white women (BMI < 27.3, n = 143), Z score was still > 2.0 in 10.3%, suggesting that the upper bound of the published reference interval may be too low. After adjustment for body mass index, BMD was greater in the forearm (9.8%), spine (8.7%), and femoral neck (14.7%) in black women (p < 0.001 at all sites). At L1, adjusted BMC in the black women was 37.4% greater than in the white women (p < 0.001). Serum calcidiol was significantly lower and serum PTH and calcitriol significantly higher in the black women. Despite this, biochemical markers of bone resorption and formation were significantly lower in the black women. We conclude that skeletally healthy older black women have a greater bone mass and lower rates of bone remodeling than a comparable group of white women. These data can serve as reference intervals for the variables measured.

Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course.

We studied the natural history of primary hyperparathyroidism in patients in whom the disease was discovered fortuitously by multichannel biochemical screening and who were selected for conservative management because they were asymptomatic, had no renal stone disease or radiographic osteitis fibrosa, and had serum calcium values below 3.00 mmol/L, serum creatinine levels below 133 mumol/L, and forearm bone density not more than 2.5 SD below the mean expected for age, sex, and race. One hundred and seventy-four patients meeting these criteria were encountered during a 10-yr period, of whom 80 (mean age, 61 yr) had adequate follow-up; they did not differ significantly in any initial characteristic from the remaining 94 patients. These 80 patients were followed for 1-11 yr (mean, 46 months; median, 38 months), during which there was no change, mean or individual, in any index of PTH secretion or any of its biochemical effects and no decline in forearm bone density apart from that expected from increased age. There were 4 deaths from causes unrelated to hyperparathyroidism, and the overall death rate was not increased. The data suggest that no change occurred in either the number of parathyroid cells or secretory set-point, the 2 principal determinants of basal PTH secretion. This implies a biphasic course, with a short period of disease progression followed by a long period of disease stability. Our data support the decision to withhold surgical intervention in such patients, but to establish this as the correct policy for all asymptomatic patients will require a controlled clinical trial.

Effects of sodium depletion on plasma renin activity and on the urinary excretion of cyclic AMP and aldosterone in hypoparathyroid patients.

The effect of sodium depletion on plasma renin activity (PRA), urinary cyclic AMP and urinary aldosterone excretion was studied in hypoparathyroid patients whose basal urinary cylic AMP excretion (urinary cAMP) was less than 50% of that observed in normal subjects. During 7 days of sodium depletion, PRA, urinary aldosterone and urinary cAMP each rose significantly. Administration of the beta-blocker propranolol, 160 mg/day, during 5 further days of sodium depletion produced a fall in PRA and urinary cAMP, but no change in urinary aldosterone excretion. The dissociation in these effects suggests that the increase in aldosterone secretion during sodium depletion may be mediated by pathways other than the renin-angiotensin and adenyl cyclase systems. There was a high degree of correlation between PRA and urinary cAMP (P less than 0.001) during the period of sodium depletion, but not significant relationship between these parameters was found during control and propranolol phases, or in control studies in normal subjects. These findings suggest that beta-adrenergic receptors have a role in mediating the effects of sodium depletion upon renin secretion and adenyl cyclase activity.

Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis.

We present iliac bone histomorphometric data after in vivo double tetracycline labeling and related biochemical data from 14 nonalcoholic men referred for evaluation of symptomatic spinal osteoporosis. Six patients had previously undiagnosed hypogonadism, and 8 had normal gonadal function and no evident etiology for osteoporosis. Bone histomorphometry revealed no differences in structural measurements or resorption indices between the 2 groups. However, compared to reference values for normal postmenopausal women, osteoblast surface, mineralizing surface, and formation rate were normal or modestly increased in the hypogonadal men and significantly reduced in the idiopathic group. There were significant corresponding differences between the 2 groups in the fasting urinary hydroxyproline to creatinine ratio, an index of bone resorption, and serum total alkaline phosphatase, an index of bone formation. Plasma 25-hydroxyvitamin D levels did not differ between the 2 groups and were above 10 ng/mL in all patients. Plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels were normal in the hypogonadal group and significantly reduced in the idiopathic group, but did not correlate with any histological measurements. The formation indices fell substantially in 3 of 4 hypogonadal men after 7-14 months of therapy with testosterone and a calcium supplement. We conclude the following. In vitamin D-replete hypogonadal men with osteoporosis, 1,25-(OH)2D synthesis is normal, and bone remodeling is modestly increased and correctable by hormone replacement therapy, as in normal postmenopausal women. In middle-aged men with idiopathic osteoporosis, there is impairment of 1,25-(OH)2D synthesis and of the recruitment and activity of teams of osteoblasts, as in postmenopausal osteoporosis.

Hypercalcemic hyperparathyroidism in hypophosphatemic rickets.

A 25-year-old white woman with sporadic hypophosphatemic rickets presented with a 7 year history of chronic mild hypercalcemia, osteitis fibrosa cystic and hypercalcemic nephropathy. Serum immunoreactive parathyroid hormone was elevated by greater than 100-fold and a 3.5 g parathyroid tumor was found at operation. Survey of the literature reveals that of 9 previous cases in which hypercalcemic hyperparathyroidism occurred in association with hypophosphatemic rickets, only two had classical x-linked familial hypophosphatemic rickets. It appears more than likely that this unusual combination of skeletal diseases represents the chance occurrence of primary hyperparathyroidism in patients with underlying x-linked familial hypophosphatemic rickets rather than a complication of phosphate therapy.