James R. Buchanan

Declining Adrenal Androgens: An Association with Bone Loss in Aging Women

Abstract Bone loss in aging women is a major contributing factor to the onset of osteoporosis. To determine whether a decline in adrenal androgen output might be important in the loss of bone with age, we studied a highly selected group of 14 women, average age 70, and measured adrenal androgens in relationship to trabecular bone density. Dehydroepiandrosterone sulfate (DHEAS) levels were used as a marker of adrenal sex steroid output while quantitative, computerized tomography was used to determine trabecular bone density. Our results showed that both bone density (r = −0.69, P < 0.01) and DHEAS levels (r = −0.68, P < 0.01) declined with age, and that DHEAS was positively correlated with bone density (r = 0.66, P = 0.01). These data emphasize the association of declining adrenal sex steroid production with declining bone density during the process of aging.

Assessment of the risk of vertebral fracture in menopausal women.

The decision to institute prophylaxis in women with menopausal osteopenia is hampered by the absence of quantitative criteria for appraising the risk of fracture in the individual. We have developed standards for assessing the risk of fracture by relating the prevalence of atraumatic vertebral compression fractures to bone density in sixty-five menopausal women, forty-nine to ninety-two years old. To define the upper limit of the spectrum of bone density, we also studied thirty-one young women, seventeen to twenty-two years old. The density of trabecular bone in a vertebral body was determined by quantitative computed tomography and expressed in terms of milligrams per milliliter of dipotassium hydrogen phosphate. Twenty-five of the menopausal women exhibited at least one fracture (range, one to six fractures), and forty had no fracture. The bone density ranged from -9 to sixty-nine milligrams per milliliter in those with fractures and from twelve to 122 milligrams per milliliter in those without a fracture. The densities in the young women averaged 173 milligrams per milliliter and ranged from ninety-five to 248 milligrams per milliliter. The percentage of subjects with fractures increased as the bone density decreased. It was zero per cent in women with a density of seventy milligrams per milliliter or more, 38 per cent in women with a density between fifty and less than seventy milligrams per milliliter, 71 per cent in those with a density between thirty and less than fifty milligrams per milliliter, and 82 per cent in women with a density of less than thirty milligrams per milliliter.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of declining renal function on bone density in aging women.

SummaryThe factors that are responsible for trabecular bone loss in aging women are not completely understood. To evaluate declining renal function as a possible factor, we studied 19 Caucasian women (average age 67) who were from 6 to 41 years postmenopausal. Trabecular bone density was quantitated by computerized tomography of the spine. Serum calcium, phosphorus, and creatinine were normal in all subjects. Creatinine clearance averaged 74 ml/min (range 38–122), decreased with age (r=−0.60,P=0.003), and was inversely related to serum creatinine (r=−0.51,P=0.01). Bivariate regression demonstrated that bone density decreased with age (r=−0.59,P=0.004); controlling for the effect of creatinine clearance weakened this correlation to r=−0.45 (P=0.03); controlling additionally for 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) reduced the correlation coefficient to r=−0.34 (P=0.11). Bone density also decreased in direct proportion to the decrement in creatinine clearance (r=0.44,P=0.03); controlling for the effects of 1,25(OH)2D and PTH reduced this correlation coefficient to r=0.34 (P=0.11). These results suggest that occult renal insufficiency may contribute to bone loss in aging women, and that this effect may be mediated in part by 1,25(OH)2D and PTH. In this age group renal function should be assessed by measuring creatinine clearance rather than the serum creatinine concentration since renal insufficiency can be masked by apparently normal circulating creatinine levels.

The effect of endogenous estrogen fluctuation on metabolism of 25-hydroxyvitamin D

SummaryTo test the hypothesis that estrogen modulates the metabolism of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24, 25-dihydroxyvitamin D (24, 25(OH)2D), we studied 20 normal premenopausal women at four consecutive weekly intervals during one menstrual cycle. Estrogen stimulation was semiquantitatively defined into baseline, lowgrade, or medium-grade categories, based on endogenous estrone and estradiol concentrations. 1,25(OH)2D increased incrementally from baseline levels of 34±3(SE) pg/ml to 39±3 pg/ml (P=0.2) with low-grade estrogen stimulation and to 43±3 pg/ml (P<0.05) with medium-grade estrogen stimulation, while 25(OH)D, 24,25(OH)2D, vitamin D binding protein, parathyroid hormone, calcium, and phosphate did not change. 24,25(OH)2D was correlated to 25(OH)D at baseline (r=0.65,P<0.01) and with low-grade estrogen stimulation (r=0.062,P<0.01), but not with medium-grade stimulation (r=0.13); these relationships are consistent with the concepts that 25(OH)D is metabolized predominantly to 24,25(OH)2D at low estrogen levels, but not at higher estrogen levels. We conclude that endogenous estrogen elevation promotes formation of 1,25(OH)2D from 25(OH)D, and that it may reciprocally inhibit synthesis of 24,25(OH)2D.

Management strategy for prevention of avascular necrosis during treatment of congenital dislocation of the hip.

We retrospectively analyzed the cases of fifty children with unilateral congenital dislocation of the hip in an attempt to determine what factors in treatment were associated with the prevention of avascular necrosis of the femoral head. All children were less than thirty-six months old at the initiation of treatment, had no other anomalies, had their entire treatment rendered at the same institution, and were followed for at least one year after reduction. Avascular necrosis occurred in 36% of the patients; in all cases definite roentgenographic signs were apparent within twelve months of reduction. No patient whose hip had grown normally during the first twelve months after reduction later had avascular necrosis. The management strategy for congenital dislocation of the hip in the child who is less than thirty-six months old should include a minimum two-week period of traction until achievement of the +2 traction station and immobilization in the so-called human position following reduction. Skeletal traction, gradually increased over several weeks to an average of 39% of body weight, usually was required to attain the +2 station. Observation of these principles should decrease the incidence of avascular necrosis and increase the probability of obtaining a normal hip.

Interaction between parathyroid hormone and endogenous estrogen in normal women

It has been hypothesized that estrogens conserve bone substance by blocking the resorbing effect of parathyroid hormone (PTH). We evaluated this hypothesis by examining the relation of circulating PTH to endogenous estrogen fluctuation during four quarters of a single menstrual cycle in 20 normal women. The hypothesis predicts that PTH should vary directly with estrogen, since PTH should increase following estrogen elevation to satisfy physiologic demands for calcium. Contrary to the predicted direct variation, PTH remained constant throughout the menstrual cycle despite sharply fluctuating estrogen levels. Furthermore, PTH was negatively associated with estrone during the early follicular (r = -.65, P less than 0.005) and late follicular (r = -.84, P less than 0.0001) phases. We attempted to determine whether this unexpected relationship between estrone and PTH signified a direct physiologic link, by excluding factors which could have spuriously engendered the inverse correlation. Stepwise multiple regression and partial correlation showed that estrone contributed significantly to circulating PTH independent of the effects of dietary calcium, 25-hydroxyvitamin D, serum calcium, 1,25-dihydroxyvitamin D, phosphate, estradiol, progesterone, and body weight. Therefore, it is possible that the inverse correlation between estrone and PTH signified a direct physiologic link, as an artifactual cause for the relationship could not be identified. These data imply that estrone interacts with PTH, but not by blocking PTH-mediated bone resorption. We conclude that estrone is associated with reduced circulating PTH through an as yet undetermined mechanism.

Adrenal androgens, sex-hormone binding globulin and bone density in osteoporotic menopausal women: is there a relationship?

The relationships among sex steroids, sex hormone binding globulin (SHBG) and vertebral bone density as measured by computerized tomography were studied in 18 post-menopausal women. A significant negative correlation was found between SHBG binding capacity (SHBG-BC) and bone density. Bone density and the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) declined with age, and SHBG-BC was correlated significantly with DHEAS concentrations. The relationship between SHBG-BC and bone density may be affected by adrenal androgen output.

Distal ulnar growth arrest

Four cases of arrest of distal ulnar physeal growth occurring in children ages 7 to 13 years had follow-up for 2 to 10 years. Each patient developed bowing of the radial diaphysis, ulnar translation of the distal radial epiphysis, and increased ulnar angulation of the distal radiocarpal joint surface. Growth discrepancies were documented in both the ulna (range 2.2 to 3.9 cm) and to a lesser extent the radius (range 0.2 to 1.6 cm) when compared to the opposite forearm in each patient. The progression of deformity appeared to be greatest during adolescence. Radial deviation and pronation were limited to varying degrees in each case. No patient had significant pain or functional impairment, but the cosmetic appearance was always displeasing. Indications for surgical treatment include increasing ulnar angulation of the distal radial articular surface, progressive loss of motion, and displeasing cosmetic appearance.

A comparison of the risk of vertebral fracture in menopausal osteopenia and other metabolic disturbances.

The risk of atraumatic compression fracture in postmenopausal women increases as vertebral trabecular bone density decreases. To determine whether the risk is similar for patients who have other metabolic disorders, we compared eight-nine patients who had various disturbances affecting bone and sixty-three postmenopausal women who had no evidence of underlying disease. Trabecular bone density was measured by quantitative computed tomography of the lumbar spine. The relationship between frequency of fracture and bone density was modeled mathematically with spline threshold, quadratic polynomial, and decaying exponential functions. Analysis of covariance showed that the diagnostic category did not influence the relationship between frequency of fracture and bone density in any of the three models. We concluded that the risk of atraumatic compression fracture, as assessed by measurement of vertebral trabecular bone density using quantitative computerized tomography, is independent of the underlying metabolic disturbance.

Stress fractures in the calcaneus of a child. A case report.

An 11-year-old girl with splastic quadriplegia, and immobilization atrophy developed a stress fracture of the calcaneus, are rare cause of heel pain in children. There was complete remission of symptoms with healing of the fracture.