maxacalcitol and Hyperplasia

The mechanisms explaining the clinical effects of direct maxacalcitol (OCT) injection into the hyperplastic parathyroid gland (PTG) in uremic patients with advanced secondary hyperparathyroidism (SHPT) were investigated by molecular and morphological examination. PTG of uremia-induced SHPT model rats were treated by a direct injection of OCT (DI-OCT) or vehicle (DI-vehicle). The changes in serum intact parathyroid hormone (intact-PTH) level, vitamin D and Ca-sensing receptor (VDR and CaSR, respectively) expression levels in PTG, and the calcium (Ca)-PTH response curve were examined; the induction of apoptosis in parathyroid cells (PTC) was also analyzed by the TUNEL method, DNA electrophoresis, and electron microscopic examination. Serum intact-PTH level following DI-OCT significantly decreased. Upregulation of both VDR and CaSR, a clear shift to the left downward in the Ca-PTH curve, and many apoptotic PTCs were observed in the DI-OCT-treated PTGs. However, these findings were not observed in the DI-vehicle-treated PTGs. Moreover, these effects were confirmed by the DI-OCT into one PTG and DI-vehicle alone into another PTG in the same rat. DI-OCT may introduce simultaneous VDR and CaSR upregulation and the regression of hyperplastic PTG, and these effects may provide a strategy for strongly suppressing PTH level in uremia-induced advanced SHPT.

Topics: Animals; Antineoplastic Agents; Bone and Bones; Calcitriol; Calcium; Cell Death; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Immunohistochemistry; Injections; Models, Animal; Organ Size; Parathyroid Glands; Parathyroid Hormone; Rats; Uremia

A high level of parathyroid hormone (PTH) is considered to be an indicator of poor prognosis and a poor quality of life of dialysis patients; therefore, an effective and safe therapy for secondary hyperparathyroidism (SHPT) has been developed.. In 20 patients with SHPT resistant to maxacalcitol (OCT) intravenously administered, all detectably enlarged parathyroid glands were treated by percutaneous maxacalcitol injection therapy (PMIT) under ultrasonographic guidance consecutively 6 times, which was followed by OCT that was intravenously administered. The clinical effects of PMIT were evaluated based on the changes in the serum intact-PTH, adjusted Ca, phosphorus, and bone marker levels, and the parathyroid gland volume determined by ultrasonography. Morphologic examination, apoptosis analysis, and PTH mRNA expression level determination by reverse transcription-polymerase chain reaction (RT-PCR) using parathyroid tissues obtained by a biopsy technique were performed.. PMIT and subsequent intravenous OCT administrations significantly decreased the serum intact-PTH level and parathyroid gland volume for at least 12 weeks after PMIT without major complications. Parathyroid tissues obtained after PMIT exhibited some partial defects of parathyroid cells, a marked increase in the number of the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells, the ladder formation determined by DNA electrophoresis, and the decrease in the PTH mRNA expression level.. PMIT is effective and safe for the treatment of refractory SHPT, and a locally high level of OCT suppresses PTH secretion and regresses parathyroid hyperplasia, which is involved in the induction of apoptosis of parathyroid cells.

Topics: Administration, Cutaneous; Adult; Aged; Apoptosis; Calcitriol; Female; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Injections, Intralesional; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uremia

In this study, we investigated the effects of direct injection (DI) of calcitriol or maxacalcitol into the hyperplastic parathyroid gland (PTG) on altered gene expression related to the advanced status of secondary hyperparathyroidism (SHPT).. Sprague-Dawley rats were 5/6-nephrectomized (uremic) or sham-operated (normal). In each uremic rat, one of the bilateral PTG was treated by DI of calcitriol (PTG(CAL)) or maxacalcitol (PTG(OCT)), and the other gland was treated with control solution (PTG(CONT)). The PTG were evaluated for levels of expression of various mRNA and immunohistochemical staining of proliferating cell nuclear antigen (PCNA).. Significant differences in levels of expression of mRNA and PCNA were confirmed between the uremic and normal groups. In PTG(CAL) and PTG(OCT), expressions of almost all mRNA and PCNA were significantly improved; both agents were able to normalize the abnormalities of the uremic PTG, in contrast to the baseline and individual PTG(CONT). However, the difference in effect between PTG(CAL) and PTG(OCT) was only small.. Our results suggest that very high concentrations of calcitriol or maxacalcitol in the PTG improve abnormal gene expression and proliferation activity of parathyroid cells, and might explain the better control of SHPT using the DI technique.

Topics: Animals; Calcitriol; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hyperparathyroidism, Secondary; Hyperplasia; Male; Nephrectomy; Parathyroid Glands; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Uremia; Vitamins

We have previously suggested that when parathyroid glands progress to nodular hyperplasia, secondary hyperparathyroidism (2HPT) may be refractory to medical treatments, including treatment with Maxacalcitol (OCT). In the present study we evaluated the clinical features and hyperplastic patterns of parathyroid glands in patients who underwent parathyroidectomy (PTx) after being withdrawn from OCT. One hundred and eighty-seven advanced 2HPT patients who had been withdrawn from OCT and required PTx were enrolled. At the start of OCT treatment, the patients had a mean age of 55.3 years and had been receiving hemodialysis (HD) for a mean period of 149 months. At the start of OCT treatment and at PTx, the mean intact PTH (i-PTH) levels were 772.8 +/- 446.0 and 855.5 +/- 420.5 pg/mL, respectively. The main reasons for withdrawal of OCT treatment were persistently high PTH (n = 148), hypercalcemia (n = 79), hyperphosphatemia (n = 65), and progressive symptoms (n = 60). We classified the parathyroid glands by hyperplastic pattern into four categories: diffuse hyperplastic gland (D), early nodularity in diffuse hyperplastic gland (EN), nodular hyperplastic gland (N), and single nodular gland (SN). The mean total excised gland weight was 2592.6 mg. Out of a total of 706 glands, 118 were classified as D, 66 as EN, 436 as N, and 86 as SN. All patients had at least one nodular hyperplastic gland or single nodular gland. The mean number of nodular hyperplastic glands and/or single nodular glands was 2.9. All hemodialysis patients with advanced OCT-refractory 2HPT who underwent PTx had at least one nodular hyperplastic gland or single nodular gland.

Topics: Aged; Bone Density Conservation Agents; Calcitriol; Combined Modality Therapy; Comorbidity; Female; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Kidney Failure, Chronic; Male; Middle Aged; Organ Size; Parathyroid Glands; Parathyroidectomy; Renal Dialysis; Ultrasonography

Direct maxacalcitol (OCT) injection into a parathyroid gland (PTG) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism (s-HPT): the upregulations of vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis. In this study, we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s-HPT. Five/six nephrectomized Sprague-Dawley rats were fed a high-phosphorus and low-calcium diet for 8 weeks. These rats were divided into four treatment groups: (1) basic uremic (at the baseline), (2) direct OCT single injection into PTGs (DI-OCT) followed by OCT intravenous administration for 4 weeks (IV-OCT), (3) direct vehicle injection and IV-OCT, and (4) no treatment for an additional 4 weeks. The effects of these treatments on serum intact-parathyroid hormone (PTH) level, PTG weight, VDR and CaSR expression levels in PTGs, and bone histomorphometric parameters were investigated. In the DI-OCT+IV-OCT group, the significant decrease in serum intact-PTH level was maintained by the following IV-OCT. A significant decrease in PTG weight and the upregulations of VDR and CaSR expression levels in PTGs were also observed. Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones. However, these findings were not observed in the other groups. These results suggest that osteitis fibrosa caused by advanced s-HPT can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI-OCT+IV-OCT.

Topics: Animals; Antineoplastic Agents; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Hyperparathyroidism, Secondary; Hyperplasia; Immunohistochemistry; Injections, Intralesional; Kidney Failure, Chronic; Male; Organ Size; Parathyroid Glands; Parathyroid Hormone; Periosteum; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Receptors, Calcium-Sensing; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity, and low contents of vitamin D and calcium-sensing receptors). Control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism, but the advanced stage of hyperplasia is considered irreversible. In the present study, dialysis patients with PTG hyperplasia underwent direct injection of calcitriol or maxacalcitol (OCT) into the PTG. Ultrasonography showed that this treatment had significantly reduced PTG volume and tissue analysis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method and DNA electrophoresis indicated that cellular apoptosis had been induced. The mechanism of apoptosis was evaluated in detail in uremic rats fed a high-phosphate diet. OCT or its vehicle was directly injected into the rats' PTGs. In the PTGs treated by OCT, there was a significantly increased number of TUNEL-positive PTCs and DNA electrophoresis revealed the characteristic ladder pattern of DNA fragmentation, both findings indicative of apoptosis. There was also a significant upregulation of both vitamin D and Ca-sensing receptors in the PTCs and a clear shift of the Ca-PTH response curve to the left and downward. None of these findings was observed in the PTGs treated by vehicle. This novel treatment is successful in causing regression of PTG hyperplasia. Thus, it is expected to significantly reduce the PTH level and ameliorate the abnormal bone turnover and mineral metabolism.

Topics: Animals; Antineoplastic Agents; Calcitriol; DNA Fragmentation; Female; Humans; Hyperplasia; Kidney Failure, Chronic; Male; Parathyroid Glands; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing; Vitamin D; Vitamins

The suppression of parathyroid hormone (PTH) secretion by the administration of 1,25-dihydroxyvitamin D [1,25(OH)2D3] and 22-oxacalcitriol (OCT) was evaluated in nude mice transplanted with human hyperplastic parathyroid tissue. The parathyroid tissue was obtained for transplantation from a patient with severe secondary hyperparathyroidism who had undergone a parathyroidectomy. Tissue specimens were transplanted into the gluteus muscle of female nude mice. Animals were divided into two groups; one group was fed a normal diet, and the other group was fed a low calcium diet during the administration of OCT and 1,25(OH)2D3. OCT and 1,25(OH)2D3 were intraperitoneally administered two times every week, for a total of eight times. Serum calcium and phosphate levels were significantly higher in the mouse administered 1,25(OH)2D3 than in the mouse administered OCT. Serum alkaline phosphatase activity was elevated similarly in the mouse administered either OCT or 1,25(OH)2D3. OCT strongly suppressed human PTH secretion from the graft in mice with normal serum calcium levels as did 1,25(OH)2D3. However, human PTH secretion from the graft was stimulated by the administration of a low-calcium diet, despite OCT and 1,25(OH)2D3 administration. In summary, OCT and 1,25(OH)2D3 suppress PTH secretion even from severe secondary hyperplastic parathyroid tissue only in mice with normal or high calcium serum levels.

Topics: Alkaline Phosphatase; Animals; Calcitriol; Calcium; Female; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Kidney Failure, Chronic; Mice; Mice, Nude; Parathyroid Glands; Parathyroid Hormone; Parathyroidectomy; Phosphates