To examine the most effective route (intravenous vs. "pulse" oral), dose (physiologic vs. pharmacologic) and long-term efficacy of calcitriol therapy for secondary hyperparathyroidism in patients with end-stage renal disease (ESRD), we randomized 19 hemodialysis patients with severe hyperparathyroidism to receive over a 36-week study period either pulse orally administered calcitriol and intravenous placebo (pulse oral group; N = 9) or intravenous calcitriol and oral placebo (intravenous group; N = 10). Calcitriol was given intermittently in a double-blinded fashion at an initial dose of 2 micrograms thrice weekly and increased as tolerated up to a maximum dose of 4 micrograms per treatment. All patients received similar daily calcium supplementation (2.5 g of elemental calcium) and low dialysate calcium (1.25 mmol/liter) throughout the study period. At the maximum tolerated calcitriol dose, serum 1,25-dihydroxyvitamin D levels were significantly greater 60 minutes following intravenous (389 pmol/liter) compared to oral administration (128 pmol/liter). In spite of the different pharmacologic profiles, intravenous and oral administered calcitriol resulted in similar reductions of serum PTH over the 36 week period of observation (P = 0.300), achieving an overall maximum average PTH reduction of 43% (P = 0.016). Long-term intensive calcitriol therapy (independent of administration route), however, failed to decrease parathyroid gland size as assessed by high resolution ultrasound and/or magnetic resonance imaging. Calcitriol therapy also failed to alter the calcium sensitivity as assessed by serial PTH measurements in response to calcium loading. Increases in serum calcium, but not calcitriol dose or parathyroid gland size, predicted decrements in serum PTH, whereas hyperphosphatemia and the level of PTH suppression derived from the PTH/ionized calcium response curves predicted refractoriness to calcitriol therapy. Episodes of hypercalcemia and hyperphosphatemia were similar in both treatment groups and limited the dose of calcitriol that could be administered. These data indicate that intermittent intensive calcitriol therapy, regardless of administration route, is poorly tolerated, fails to correct parathyroid gland size and functional abnormalities, and has a limited ability to achieve sustained serum PTH reductions in end-stage renal failure patients with severe hyperparathyroidism.

To examine the possibility that uremia alters the relationship between bioactive PTH serum concentrations and its osseous end-organ response, we evaluated the relationship between circulating intact PTH and bone turnover in 39 end-stage renal disease patients with hyperparathyroid-mediated bone disease of varying severity. We excluded from analysis patients with coexistent defects in mineralization to insure that bone remodeling indices primarily reflected the effects of PTH. The distribution of serum PTH levels ranged from normal to markedly elevated. Regression analysis between circulating intact PTH concentrations, measured by a two-site immunoradiometric assay, and osseous indices of hyperparathyroidism, determined by quantitative bone histological analysis of iliac crest bone biopsies, showed that bioactive serum PTH levels correlated linearly with bone formation (r = 0.836), woven osteoid volume (r = 0.718), and marrow fibrosis (r = 0.856), and nonlinearly with parameters of bone resorption (r = 0.760). From these functional relationships, we found that the average serum intact PTH level of approximately 165 pg/mL, a value that exceeds the upper limit of intact PTH in nonuremic subjects (65 pg/mL) by 2.5-fold, defines the upper normal limit of bone turnover in uremic subjects. Indeed, the average serum PTH concentrations reached 500 pg/mL before histological evidence of severe hyperparathyroidism developed in uremic subjects. These findings demonstrate that elevated PTH concentrations are necessary to maintain normal bone remodeling in the uremic setting. Consequently, it may not be necessary to attain normal serum intact PTH levels to control the osseous manifestations of PTH excess in uremic subjects.

Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case‐control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case‐control status (159 prostate cancer cases/156 controls). Hair‐patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 ± 6.1 vs. 14.9 ± 4.8 pg/ml, P = 0.02). Conversely, DHT‐related ratios were greater among controls (P = 0.03 for DHT/T and P = 0.01 for DHT/free T). Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 ± 5.5 and 16.2 ± 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 ± 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma. In addition, although no differences in hair patterning were detected between cases and controls within this older population, further research (i.e., prospective trials or case‐control studies among younger men) may be necessary to determine if hair patterning serves as a viable biomarker for this disease, especially given the strong association between free T levels and baldness.

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