Proliferation of osteoclasts in rat bone following bleeding and femoral fractures

Summary There is a significant transient increase in the number of osteoclasts in intact bone after bleedings and fractures in rats. This rise in the osteoclast population might be due to an increased parathyroid activity released by the trauma, but other factors may be involved. Both bleeding and fractures in rats are followed by hypercalcemia.     

Prostaglandin-mediated hypercalcemia: A paraneoplastic syndrome

Summary Evidence has been presented for prostaglandin-mediated hypercalcemia and bone resorption in malignancies of both, experimental animals and man. Occurrence of hypercalcemia in cancer patients is known for a long time, but its pathogenesis has been poorly understood so far. Besides ectopic parathyroid hormone secretion by tumors, an osteoclastactivating factor released from leukocytes and direct bone destruction by tumor cells, prostaglandins of the E series have to be considered as one of the candicates involved in the pathomechanism of hypercalcemia and osteoclastic osteolysis in cancer patients. This new concept on the pathophysiology of cancer-associated hypercalcemia has implications for the diagnosis and management of this common complication of neoplastic disease.

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Abbreviations used cAMP cyclic adenosine 3:5-monophosphate - cr creatinine - NSAI drugs nonsteroidal antiinflammatory drugs - OAF osteoclast-activating factor - PG prostaglandin - 15-K-H₂-PG's 15-keto-13,14-dihydro-PG's - H₂-PGE₂ 13,14-dihydro-PGE₂ - PGE-M 7-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid - PGF-M 5, 7-dihydroxy-11-ketotetranorprostane-1,16-dioic acid - PTH parathyroid hormone - Tx thromboxane     

Evidence for abnormal regulation of circulating 1α,25-dihydroxyvitamin D in patients with pulmonary tuberculosis and normal calcium metabolism

Summary Available evidence indicates that hypercalcemia in pulmonary tuberculosis results from increases in circulating 1α,25-dihydroxyvitamin D [1α,25(OH)₂D]. To further characterize vitamin D metabolism in this disorder, the effects of vitamin D, 100,000 units a day for 4 days, were compared in 25 normal subjects and 11 patients with active pulmonary tuberculosis who were normocalcemic and had not had hypercalcemia. Serum calcium, phosphorus, 25-hydroxyvitamin D (25-OHD) and 1α,25(OH)₂D were measured. Whereas vitamin D increased mean serum 25-OHD from 20±2 (±SE) to 40±5 ng/ml (P<0.001) and did not change mean serum 1α,25(OH)₂D in the normals (33±2 vs. 31±2 pg/ml), it increased mean serum 25-OHD from 21±4 to 55±13 ng/ml (P<0.05) and mean serum 1α,25(OH)₂D from 28±2 to 35±3 pg/ml (P<0.05) in the patients. Serum calcium was normal and remained within the normal range in all subjects and patients. The findings indicate that there is a modest but significant abnormality in the regulation of circulating 1α,25(OH)₂D in normocalcemic patients with pulmonary tuberculosis. The results are similar to those previously reported by us in normocalcemic patients with sarcoidosis.     

Evaluation of the first Ergocalciferol-derived, non hypercalcemic anti-cancer agent MT19c in ovarian cancer SKOV-3 cell lines

Objective

In human trials calcitriol and its analogs displayed unacceptable systemic toxicities including hypercalcemia. This study was designed to evaluate a novel non-hypercalcemic vitamin-D derivative (MT19c) and its anticancer effects in cultured ovarian cancer cell model.

Methods

We modified the Ergocalciferol structure to generate MT19c, a heterocyclic vitamin-D derivative. Hypercalcemic liabilities of MT19c were assessed by estimating the blood calcium levels in drug treated animals. VDR agonistic or antagonistic properties of MT19c were determined via a VDR-coactivator binding assay. The anticancer effects of MT19c were evaluated by (i) cytotoxicity studies in cancer cell lines and the National Cancer Institute (NCI₆₀) cell lines, (ii) identification of apoptosis markers by microscopy and western blots, (iii) cell cycle analysis, and (iv) by studying the insulin receptor substrate-1/2 (IRS1/2) signaling in ovarian cancer cells (SKOV-3) by western blotting.

Results

MT19c treatment did not cause hypercalcemia in mice and showed minor VDR antagonistic activity. In a NCI₆₀ screen MT19c revealed cell-type specific growth inhibition. MT19c displayed superior cytotoxicity to cisplatin, calcitriol, EB1089 and Iressa in SKOV-3 cell-lines and was comparable to Taxol in our in vitro assays. In SKOV-3 cells MT19c showed caspase dependent apoptosis, DNA fragmentation and cell cycle arrest. MT19c did not alter VDR but downregulated the IGFR/IRS-1/2-MEK-ras-ERK1/2-pathway via activated TNFα-receptor/SAPK/JNK component.

Conclusion

Our results demonstrate how structural optimization of the vitamin-D scaffold leads to identification of a non-hypercalcemic compound MT19c which exerts cytotoxicity in vitro based on a VDR-independent signaling pathway and displays potent anti-cancer activity in ovarian cancer cell models.     

Total parathyroidectomy without autotransplantation in dialysis patients and renal transplant recipients, long-term follow-up evaluation

Background

Persistent secondary hyperparathyroidism not responding to medication is treated successfully with surgical excision of parathyroid glands (total parathyroidectomy [PTX]). PTX without autotransplantation of parathyroid glands excludes the risk for recurrence of hyperparathyroidism.

Methods

During the years 2002 to 2005, 36 total parathyroidectomies were performed in 33 patients: 21 dialysis patients because of end-stage renal disease and 12 renal transplant recipients.

Results

PTX without autotransplantation was performed successfully in 33 patients, whereas 3 patients were reoperated for remaining parathyroid glands. Immediate improvement of clinical symptoms and a decrease of serum calcium and parathormone levels were observed after surgical procedures. Oral replacement treatment with vitamin D (1a-calcidiol) and calcium was commenced and long-term follow-up evaluation (23.5 ± 7.6 mo) showed that calcium homeostasis was controlled adequately.

Conclusions

PTX without autotransplantation is a safe and effective surgical procedure for the treatment of resistant secondary hyperparathyroidism with immediate response of clinical symptoms. Replacement treatment with vitamin D and calcium provides satisfactory coverage of individual needs.     

Humoral hypercalcemia revealing a malignant non hodgkin lymphoma

INTRODUCTION: Hypercalcemia is a rare complication of non-Hodgkin lymphoma. Usually, hypercalcemia occurs late in the disease course, except for high-grade lymphoma. Most often hypercalcemia is related to excessive level of circulating PTH-rP or sometimes, 1,25(OH)2D3. Concomitant high plasmatic concentration of PTH-rP and 1,25(OH)2D3 is uncommon. EXEGESIS: We report the case of a 82-year-old man who presented with abdominal pain and weight loss, leading to the diagnosis of diffuse large-B-cell lymphoma (high-grade lymphoma) associated with symptomatic hypercalcemia (3.21mmol/l). PTH-rP and 1,25(OH)2D3 plasmatic levels were high. Calcium concentration was normalized with glucocorticoids and sequential chemotherapy. CONCLUSION: This case report confirms that hypercalcemia, as consequence of excessive plasmatic level of PTH-rP secreted by tumoral cells, can occur early in the course of high-grade lymphoma. Glucocorticoids and chemotherapy are the best treatment options.     

In vitro bone resorption activity produced by a hypercalcemic adenocarcinoma tumor line (CAC-8) in nude mice

Summary Tumor extracts and conditioned tissue culture media from a canine adenocarcinoma tumor line (CAC-8) propagated in nude mice significantly increasedin vitro bone resorption in neonatal mouse calvaria as measured by release of previously incorporated⁴⁵Ca.In vitro bone resorption activity was induced in a dose-dependent manner, was not suppressible by indomethacin, and was heat- and acid-stable. Gel exclusion chromatography demonstrated peak bone resorbing activity at a relative molecular mass of approximately 28,000. The parathyroid hormone (PTH) antagonist (^8,18norleucine,³⁴tyrosine) bovine PTH (3–34) amide did not inhibit CAC 8-stimulated or (1–34) bPTH-induced bone resorption. There was an increased number of tartrate-resistant, acid phosphatase-positive cells in calvariae exposed to CAC-8 extract. Ultrastructural evaluation of calvaria revealed hypertrophy and maturation of osteoclasts in calvaria exposed to CAC-8 extract. The maturation effects included close contact to bone surfaces and the presence of clear zones and ruffled borders in osteoclasts. Similar structures were observed infrequently in osteoclasts of control calvaria. These data demonstrate that the tumor line (CAC-8) contained activity capable of stimulatingin vitro bone resorption by increasing osteoclast numbers and the activity of existing osteoclasts.     

Treatment of severe hypercalcemia with peritoneal dialysis in an infant with end-stage renal disease

Recurrent and unusually severe hypercalcemia was observed in an infant undergoing continuous cyling peritoneal dialysis and receiving oral calcitriol and calcium carbonate. Rapid correction was achieved with peritoneal dialysis using a calcium-free dialysis solution.     

HYPERCALCEMIA AND LIPOID PNEUMONIA

A 49-year-old man with an 11 year history of NIDDM presented hypercalcemic and with acute on chronic renal failure. His only symptoms were mild anorexia and nausea. Four years previously he had been diagnosed as haying lipoid pneumonia, with classical histological findings. On this admission, serum parathyroid hormone was suppressed and 1,25 dihydroxyvitamin D levels elevated. The cause of his hypercalcemia presumably was ectopic 1 hydroxylation of 25 hydroxyvitamin D in the chronic granulomata in his lungs. It should be emphasised that any chronic granulomatous disease, and not just sarcoidosis, may be a cause of hypercalcemia.     

益钙宁治疗高钙血症的疗效观察

用鳗降钙素类似物－益钙宁治疗１０例次７例患者高钙血症。经７天观察，血钙在４小时及２４小时均显著降低，但４８小时回升到近治疗前水平，出现“脱逸”现象，随后几天血钙波动在较高水平。