Osteoporosis in primary biliary cirrhosis: effects of 25-hydroxyvitamin D3 treatment.

Bone histology, bone mineral content, and calcium absorption were evaluated in 10 patients with primary biliary cirrhosis and osteopenia, before and after 1 yr of treatment with oral 25-hydroxycholecalciferol. Before treatment, quantitative histomorphometric analysis of full-thickness iliac crest bone biopsy specimens with double-tetracycline labeling demonstrated that 9 of 10 patients had osteoporosis. None had osteomalacia. Fasting intestinal calcium absorption correlated well with trabecular bone volume (r = 0.85). Bone mineral content measured by 125I-photon absorption was low in 6 of 10 patients, and it correlated poorly with iliac crest trabecular bone volume. After 1 yr of treatment with oral 25-hydroxyvitamin D3, bone mineral content fell in all 8 patients who were restudied. Iliac crest trabecular bone volume increased in 3 patients, 2 of whom had the greatest pretreatment impairment in calcium absorption, but fell in 5. Bone fractures continued to occur in 3 of 5 patients who were alive after 1 yr and developed for the first time in a sixth patient. We conclude that 25-hydroxyvitamin D3 is ineffective in reversing the bone thinning in the majority of primary biliary cirrhosis patients, but it may be helpful in a few selected patients.

C-cell hyperplasia and medullary thyroid carcinoma in the rat. An immunohistochemical and ultrastructural analysis.

Medullary thyroid carcinoma (MTC) is a distinctive neoplasm which is derived from the calcitonin-producing intrathyroidal C-cell system and which develops commonly in untreated rats of various strains. Thyroid glands of Long-Evans rats ranging in age from 3 months to 3 years showed a spectrum of C-cell proliferative abnormalities. As compared to 3-month-old control rats, thyroids from 9- to 12-month-old animals exhibited mild diffuse C-cell hyperplasia (CCH). Thyroids from animals ranging from 1 to 3 years of age exhibited progressively more severe C-cell abnormalities including severe diffuse CCH, nodular CCH, and/or MTC. In contrast to the normal basal serum calcitonin levels in controls and in animals with mild diffuse CCH, animals with severe diffuse CCH, nodular CCH, or MTC had elevated basal serum calcitonin values. Nodular CCH was characterized by the replacement and enlargement of individual follicles by C-cells. Larger foci of nodular CCH were characterized by similar changes in multiple adjacent follicles or by an irregular expansion of individual follicles. MTC was characterized by penetration of the follicular basal lamina by C-cells with extension into the adjacent thyroid stroma. In addition to the high incidence of thyroidal C-cell abnormalities, diffuse and/or nodular parathyroid hyperplasia was commonly found. There was no evidence of chronic renal failure in these animals, and the serum calcium levels were within normal limits. Although the stimulus for the initial C-cell proliferation remains unknown, the appearance of MTC is preceded by relatively prolonged phases of CCH. These findings are essentially identical with those noted in human familial MTC and indicate that the rat provides a useful model system for studying the regulation of C-cell proliferation during the processes of neoplastic development and progression.

Systemic effects of the VX2 carcinoma on the osseous skeleton. A quantitative study of trabecular bone.

The skeleton of rabbits bearing the transplantable VX2 carcinoma has been studied by a combination of radiographic and histomorphometric techniques. It has previously been shown that this tumor produces and secretes large amounts of prostaglandin E2. In vivo experiments, as well as cell and organ culture studies, have led to the conclusion that the hyerpcalcemia observed in tumor-bearing rabbits is due to excessive secretion of prostaglandin E2 by the tumor and its subsequent action on bone throughout the organism. Our new findings reveal (1) no evidence of local invasion of bone by the VX2 tumor or osseous metastases; (2) radiographic evidence of generalized osteopenia; (3) histomorphometric documentation in trabecular bone of reduced volume density of bone matrix, consistent with increased resorption in trabecular bone at sites distant from tumor; and (4) a marked generalized reduction in surface density of osteoblastic layers, volume density of osteoid, osteoid seam thickness, and surface density of osteoid. These findings in trabecular bone of iliac crest and vertebra offer quantitative data in support of the conclusion that VX2 carcinoma affects skeletal metabolism systemically.