Increase in bone mass after correction of vitamin D insufficiency in bisphosphonate-treated patients.

OBJECTIVE: To assess the relative contribution of vitamin D insufficiency to loss of bone mineral density (BMD) in patients taking bisphosphonates. METHODS: Patients were eligible for inclusion if they had osteoporosis or osteopenia and demonstrated a decline in BMD during the preceding year while taking stable doses of alendronate or risedronate, plus supplemental calcium and vitamin D. Patients with previously known secondary causes of osteoporosis were excluded from the study. Eligible patients underwent prospective measurement of bilateral hip and lumbar spine BMD by dual-energy x-ray absorptiometry, serum 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, intact parathyroid hormone, osteocalcin, and thyroid-stimulating hormone (thyrotropin), and urinary calcium:creatinine ratio. RESULTS: Annual BMD was assessed in 175 previously bisphosphonate-responsive patients with low BMD. Of the 175 patients, 136 (78%) had either a significant interval increase or no change in BMD, whereas 39 (22%) had a significant decrease. Of the 39 patients who lost BMD, 20 (51%) had vitamin D insufficiency (25-OHD <30 ng/mL). After a single course of orally administered vitamin D2 (500,000 IU during a 5-week period), the 25-OHD level returned to normal in 17 of the 20 vitamin D-insufficient patients and was associated with significant (P<.02) 3.0% and 2.7% increases in BMD at the lumbar spine and the femoral neck, respectively. Failure to normalize the serum 25-OHD level was associated with further loss of BMD. CONCLUSION: Vitamin D insufficiency was the most frequently identified cause of bone loss in patients with declining BMD during bisphosphonate therapy. Correction of vitamin D insufficiency in these patients led to a significant rebound in BMD.

Vitamin D therapy.

The fat-soluble vitamin D prohormones, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), are essential for the efficient intestinal absorption of calcium and phosphate and the subsequent mineralization of bone. Inadequate vitamin D leads to chronic secondary hyperparathyroidism and osteoporosis. The increasing prevalence of osteoporosis has paralleled a pandemic of vitamin D insufficiency. Based on observational and prospective trials with clinical end points, the standards for vitamin D sufficiency have been recently revised. All patients with osteopenia or osteoporosis should be monitored with a reliable assay to maintain serum 25-hydroxyvitamin D levels more than 32 ng/dL. Patients who are taking bisphosphonates and those with coexisting primary hyperparathyroidism are not exempt from taking supplemental vitamin D.

Ovarian hyperstimulation syndrome caused by an FSH-secreting pituitary adenoma.

BACKGROUND: A 40-year-old woman presented with galactorrhea and oligomenorrhea. She had a history of multiple ovarian cysts and pelvic pain. INVESTIGATIONS: Laboratory evaluation included measurements of the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free endogenous T4, the glycoprotein hormone alpha subunit, cortisol, adrenocorticotropic hormone, and insulin-like growth factor I. Radiological studies included MRI of the pituitary. DIAGNOSIS: Ovarian hyperstimulation syndrome caused by a pituitary adenoma, secreting follicle-stimulating hormone. MANAGEMENT: The patient underwent trans-sphenoidal resection of the adenoma, with subsequent normalization of hormonal values and symptoms.

Cinacalcet in the management of tumor-induced osteomalacia.

UNLABELLED: Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO and FGF-23-mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of bone healing in one of the two patients. INTRODUCTION: Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting, which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the phosphate and vitamin D-regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathyroidism, would be an effective adjuvant in the treatment of TIO. MATERIALS AND METHODS: Two subjects with presumed TIO in whom the tumor was not located after extensive testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet. RESULTS: Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated. On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan and lack of osteomalacia as assessed by histomorphometry. CONCLUSIONS: These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased.

Vitamin D-mediated hypercalcemia in slack skin disease: evidence for involvement of extrarenal 25-hydroxyvitamin D 1alpha-hydroxylase.

UNLABELLED: A case of granulomatous slack skin disease is presented in which we studied the possible involvement of extrarenal 1,25(OH)2D in the pathogenesis of the patient's hypercalcemia. Immunolocalization of 1alpha-OH in skin showed simultaneous dysregulation in epithelial and granulomatous cells. INTRODUCTION: Granuloma-forming diseases such as sarcoidosis are associated with extrarenal synthesis of active 1,25-dihydroxyvitamin D [1,25(OH)2D]. Here we describe a case of granulomatous slack skin disease in which we have studied the possible involvement of extrarenal synthesis of 1,25(OH)2D in the pathogenesis of the patient's hypercalcemia. The aim of the study was to clarify the etiology of hypercalcemia in this patient. MATERIALS AND METHODS: This was a case study of a 19-year-old man with a T-cell lymphoproliferative disorder diagnosed as granulomatous slack skin disease who presented with hypercalcemia and raised serum 1,25(OH)2D. Analysis of expression of the enzyme 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase), which catalyzes synthesis of 1,25(OH)2D, was carried out by immunohistochemical analysis of involved and uninvolved skin. Approval was granted by the Mayo Foundation Institutional Review Board and Biospecimens Subcommittee. RESULTS: In uninvolved skin, expression of 1alpha-hydroxylase was confined to the basal layer of the epidermis, whereas slack skin showed overexpression of the enzyme in dermal granulomata and basal cells of the epidermis. CONCLUSIONS: Hypercalcemia associated with granulomatous slack skin syndrome seems to be caused by dysregulation of 1alpha-hydroxylase expression in both epidermal and dermal granulomatous cells. This contrasts with psoriasis and sarcoidosis of the skin, in which overexpression of the enzyme is restricted to keratinocytes and granulomata, respectively.

Dermatologic manifestations of hypopituitarism.

Hypopituitarism is characterized by diminished or absent secretion of one or more pituitary hormones. The clinical features of hypopituitarism vary depending on age, rapidity of onset, hormones involved, and degree of deficiency. Dermatologic signs of hypopituitarism may involve alterations in pigmentation, the epidermal and dermal skin structures, and the pilosebaceous unit. We describe the causes and presentation of hypopituitarism with an emphasis on its dermatologic manifestations.

Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease.

OBJECTIVE: Osteoporosis is a common complication of Crohn's disease (CD). Glucocorticoid use and detrimental effects of inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) can lead to osteoporosis. The aim of this study was to assess the ability of treatment with the TNF-alpha antagonist infliximab to increase bone formation as measured by surrogate markers of bone turnover in patients with active CD. METHODS: Sera from 38 prospectively enrolled CD patients were examined for levels of bone alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTX), immunoreactive parathyroid hormone (iPTH), calcium, and pro-inflammatory cytokines at baseline and 4 weeks following infliximab infusion. Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and glucocorticoid dose also were collected. RESULTS: In this cohort, CDAI and IBDQ scores were significantly improved at week 4 (P<0.001). Infliximab therapy was associated with an increase in BAP, a marker of bone formation (P=0.010), whereas NTX, a marker of bone resorption, was not increased (P=0.801). Among 22 patients who were taking glucocorticoids, mean glucocorticoid dose decreased 36% (P<0.001; -7.9 mg). CONCLUSIONS: Treatment with infliximab was associated with increased markers of bone formation (BAP) without increasing bone resorption (NTX). This effect may be due to a beneficial effect of TNF-alpha blockade on bone turnover, a beneficial effect on CD activity resulting in decreased glucocorticoid dose, or both. Studies of longer duration are needed to assess the effect of infliximab on bone mineral density.

Pigmented adrenocortical carcinoma: case report and review.

Darkly pigmented adrenocortical neoplasms are rare tumors that are often referred to as "black adenomas," indicative of both their pigmented nature and their invariably benign clinical behavior in previously reported cases. We herein describe an exceptional case of a malignant pigmented adrenocortical neoplasm, with late recurrence and metastasis. At age 53, this female patient was diagnosed with Cushing's syndrome and underwent a laparoscopic right adrenalectomy, revealing a 3 cm well-circumscribed, darkly pigmented adrenocortical tumor. The tumor exhibited several atypical histologic features and was diagnosed as an atypical pigmented adrenal cortical neoplasm of uncertain malignant potential. Eight years later, the patient developed clinical and biochemical evidence of recurrent Cushing's syndrome, and imaging studies revealed the presence of several masses in the right retroperitoneum. At subsequent exploratory laparotomy, three separate tumor nodules exhibiting varying degrees of pigmentation and ranging from 2.2 to 3.3 cm maximum dimension were excised. Histologically, the tumor nodules were consistent with local recurrence/metastasis of the patient's previously excised pigmented adrenocortical neoplasm.

Diffuse venous thromboemboli associated with IVIg therapy in the treatment of streptococcal toxic shock syndrome: case report and review.

Streptococcal toxic shock syndrome (STSS) is a severe invasive disease with a 40-80% mortality rate. Inflammatory cytokines induced by streptococcal pyrogenic exotoxins (SPEs) produce the clinical manifestations of a flu-like syndrome, followed by high fevers and multiorgan failure. Previously published reports have described the use of intravenous immunoglobulin (IVIg) as adjunctive treatment for STSS. However, concerns have been raised about the thromboembolic complications of this therapy. We report a severe case of STSS treated with two adjunctive courses of IVIg complicated by severe bilateral pulmonary thromboemboli. To our knowledge, this is the only reported case of thromboemboli associated with IVIg for STSS. The results of this case support the cautious use of IVIg for STSS and demonstrate the need for controlled trials to determine the appropriate timing, dosage, and course of treatment.