[Prostate Cancer Diagnosed during Androgen Replacement Therapy for Late-Onset Hypogonadism Treatment: A Case Report].

We report a 60-year-old man with prostate cancer diagnosed during androgen replacement therapy (ART) for late onset hypogonadism after surgery for pituitary adenoma. He was refered to the department of urology since prostate specific antigen values were elevated after 6 months of ART. After the diagnosis of prostate cancer, ART was discontinued, and robot-asssited laparoscopic radical prostatectomy with pelvic lymphadenoctomy was performed. Pathological examination revealed Gleason score 4 + 5 prostate adenocarcinoma with seminal vesicle invasion and lymph node metastasis(pT3bN1). He has stayed biochemically and radiologically disease-free 33 months postoperatively.

Hyponatremia in an Elderly Patient due to Isolated Hypoaldosteronism Occurring after Licorice Withdrawal.

Hyponatremia is one of the most common electrolyte disorders encountered in the elderly. We present the case of an 81-year-old man who developed hyponatremia due to isolated hypoaldosteronism occurring after licorice withdrawal. He had severe hypokalemia with hypertension and was diagnosed with pseudoaldosteronism. He had been taking a very small dose of licorice as a mouth refresher since his early adulthood. Five months after licorice withdrawal, he developed hypovolemic hyponatremia, which was resolved with administration of fludrocortisone acetate. Our experience with this case suggests that isolated hypoaldosteronism occurring after licorice withdrawal should be considered as a potential cause of hyponatremia in elderly patients.

Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients.

BACKGROUND: The interactions between kidney and thyroid functions have been known for many years; however, there are few studies on the extent of the improvements and long-term changes of renal function after thyroid hormone replacement therapy (THRT) in chronic kidney disease (CKD) patients. The purpose of this study was to determine how THRT affects the estimated glomerular filtration rate (eGFR) in CKD patients with primary hypothyroidism. METHODS: A retrospective investigation was performed on 51 Japanese patients (15 men and 36 women) with primary hypothyroidism. The changes in eGFR after THRT were examined according to the existence of CKD and severity of thyroid function. RESULTS: eGFR increased rapidly over the first 6 months after THRT in CKD patents, which was followed by a plateau. There was a correlation between eGFR and the severity of hypothyroidism, which was independent of age, and eGFR in severely hypothyroid patients significantly increased up to levels that were similar to mildly hypothyroid patients after THRT. eGFR improved more in the lower initial eGFR group and increased about 30 % in CKD patients (47.5 ± 7.7 vs. 62.1 ± 9.5 ml/min/1.73 m(2), P < 0.01). Moreover, eGFR in CKD patients with mild to moderate hypothyroidism was significantly increased compared to that in non-CKD patients. CONCLUSION: Our data suggested that hypothyroidism contributed to the reduction in eGFR, especially in CKD patients; therefore, patients with CKD should positively be examined for thyroid function, and appropriate THRT should be started if needed.

A case of neurofibromatosis type 1 coinciding with bilateral pheochromocytomas, multiple gastrointestinal stromal tumors, and malignant peripheral nerve sheath tumor.

Neurofibromatosis type 1 (NF1) is associated with benign and malignant neoplasms, but the coincidence of abdominal neoplasms is rare. A 65-year-old woman with NF1 had episodes of nausea, tachycardia, hypertension, and loss of consciousness. Bilateral adrenal tumors were detected by abdominal computed tomography, and plasma and urinary catecholamine levels were elevated. Open bilateral adrenalectomy and histological findings revealed bilateral pheochromocytomas (PCCs). Furthermore, malignant peripheral nerve sheath tumor (MPNST) and multiple gastrointestinal stromal tumors (GISTs) were incidentally found in the abdominal cavity. Early diagnosis of abdominal neoplasms in NF1 patients is important because of the risk of malignancy, organic complications and hemorrhagic-obstructive complications.

Matrix extracellular phosphoglycoprotein is expressed in causative tumors of oncogenic osteomalacia.

Oncogenic osteomalacia (OOM), or tumor-induced osteomalacia, is a rare disease characterized by renal phosphate wasting and osteomalacia. It arises due to the secretion of fibroblast growth factor 23 (FGF-23) from causative tumors. Matrix extracellular phosphoglycoprotein (MEPE) is predominantly expressed in odontoblasts, osteoblasts, and osteocytes. Although the presence of MEPE mRNA has been reported in some OOM tumors, little is known about the prevalence of MEPE expression in OOM tumors. In this study, the expression of MEPE and FGF-23 in OOM tumors was investigated at the transcriptional and translational levels. Eleven causative OOM tumors were analyzed by quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry for MEPE and FGF-23 expression. Hemangiopericytomas and giant cell tumors, pathological diagnoses that are common in cases of OOM, were obtained from non-osteomalacic patients and analyzed as controls. The gene expression level of FGF23 and MEPE in OOM tumors was 10(4)- and 10(5)-times higher, respectively, than in non-OOM tumors. Immunohistochemical staining revealed that FGF-23 protein was expressed in all OOM tumors, and MEPE was expressed in 10 out of 11 OOM tumors. Thus, MEPE expression was common in OOM tumors, similar to FGF-23. These results indicate that, in addition to the hypophosphatemic effects of FGF-23, MEPE or the MEPE-derived acidic serine aspartate-rich MEPE-associated motif peptide may contribute to decreased bone mineralization in OOM patients.

A case of hepatitis C-associated osteosclerosis with xanthogranulomatous cholecystitis.

A 62-year-old woman presented with a markedly increased serum ALP level of skeletal origin during a regular follow-up of chronic hepatitis C. Serum calcium, phosphorus, and intact-PTH levels were normal and bone turnover markers were increased. Her generalized bone density was diffusely increased. These findings were consistent with hepatitis C-associated osteosclerosis (HCAO). She underwent cholecystectomy, as gallbladder cancer was suspected; however, histopathological findings demonstrated xanthogranulomatous cholecystitis. After cholecystectomy, serum ALP level and bone turnover markers were gradually decreased. This may indicate the existence of a novel osteogenic factor in the gallbladder in HCAO.

A case of Marinesco-Sjögren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial.

Circulating C-type natriuretic peptide (CNP) rescues chondrodysplastic CNP knockout mice from their impaired skeletal growth and early death.

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.

The levels of somatostatin receptors in causative tumors of oncogenic osteomalacia are insufficient for their agonist to normalize serum phosphate levels.

Oncogenic osteomalacia (OOM) is a rare disease characterized by renal phosphate wasting and osteomalacia and is caused by the secretion of fibroblast growth factor 23 (FGF-23) from causative tumors. Scintigraphy with octreotide, which binds to somatostatin receptors (SSTRs), is a useful way to locate causative tumors in OOM patients. However, the therapeutic effects of octreotide acetate are still controversial. Two OOM patients were administered octreotide acetate intramuscularly. Ten causative OOM tumors, including two resected from the patients participating in the octreotide administration study, were examined for expression of genes encoding SSTRs by quantitative real-time RT-PCR and immunohistochemistry. Octreotide therapy did not improve hypophosphatemia in either case, despite temporal decreases in FGF-23 levels in one patient. The mean expression levels of SSTR1, SSTR3, and SSTR5 were similar in the OOM and non-OOM tumors. Expression of SSTR2 was significantly higher in the OOM tumors than in the non-OOM tumors. Immunohistochemical examinations revealed the presence of SSTR2A, SSTR2B, and SSTR5 in both the OOM and non-OOM tumors. The expression of SSTR genes in OOM tumors contributes to positive imaging using octreotide scintigraphy. However, the levels of SSTRs seem to be insufficient for the octreotide therapy to improve hypophosphatemia. Further studies are needed to clarify the mechanisms by which FGF-23 secretion from OOM tumors is suppressed by octreotide acetate.

Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias.

Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Furthermore, we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in a mouse model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, to elucidate whether or not the systemic administration of CNP is a novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by iv administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans.

Effects of risedronate or alfacalcidol on bone mineral density, bone turnover, back pain, and fractures in Japanese men with primary osteoporosis: results of a two-year strict observational study.

Although osteoporosis in men is already a major public health problem, there is still a dearth of data about the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. Therefore, the objective of our study was to investigate the effects of risedronate on bone mineral density (BMD), bone turnover, back pain, and fractures in these patients prospectively for two years (at baseline, three months, six months, twelve months, and twenty-four months) both longitudinally and compared with those of alfacalcidol. The subjects enrolled for this study were 66 Japanese male patients with untreated primary osteoporosis (mean age 63.52 +/- 8.7 years), who were divided into two groups (44 with risedronate and 22 with alfacalcidol). We measured BMD by dual energy X-ray absorptiometry at three sites-the lumbar spine, femoral neck, and distal radius. Risedronate treatment significantly increased BMD at the lumbar spine and at the femoral neck, reduced bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), and reduced back pain, both longitudinally and compared with alfacalcidol treatment. We observed a lower rate of incident fracture in risedronate users. However, multiple logistic regression analysis revealed that this trend was not statistically significant, possibly because of the small number of patients enrolled. These potentially beneficial effects of risedronate on bone in male patients with primary osteoporosis suggest the possibility that osteoporosis should be treated with risedronate regardless of gender in order to effectively prevent subsequent osteoporotic fractures.

A case of cortisol producing adrenal adenoma without phenotype of Cushing's syndrome due to impaired 11beta-hydroxysteroid dehydrogenase 1 activity.

This report concerns a case of cortisol-producing adrenocortical adenoma without the phenotype of Cushing's syndrome. A left adrenal tumor was incidentally detected in this patient. A diagnosis of adrenal Cushing's syndrome was based on the results of endocrinological and radiological examinations, although she showed none of the physical signs of Cushing's syndrome, glucose intolerance, hypertension or dyslipidermia. After a successful laparoscopic left adrenalectomy, the pathological diagnosis was adrenocortical adenoma. Slow tapering of glucocorticoids was needed to prevent adrenal insufficiency after surgery, and the plasma ACTH level remained high even though the serum cortisol level had reached the upper limit of the normal range. Further examination showed a urinary THF + allo-THF/THE ratio of 0.63, which was lower than that of control (0.90 +/- 0.13, mean +/- SD). Serum cortisol/cortisone ratios after the cortisone acetate administration were also decreased, and the serum half-life of cortisol was shorter than the normal range which has been reported. These findings indicated a partial defect in 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activity, which converts cortisone to cortisol. Our case suggests that a change in 11beta-HSD1 activity results in inter-individual differences in glucocorticoid efficacy.

Efficacy of risedronate in Japanese male patients with primary osteoporosis.

OBJECTIVE: Although osteoporosis in men previously was relatively neglected, bisphosphonates have been strongly suggested as potent therapeutic agents. However, there are few studies on the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. The aim of our study was to prospectively evaluate the effects of risedronate on bone mineral density (BMD) and bone turnover in Japanese male patients. METHODS: According to the therapeutic regimen, the subjects were divided into two groups (group A, 22 with risedronate; group B, 10 without risedronate). During a one-year study duration, we measured bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) every 3 months, and BMD at 7 sites by dual-energy X-ray absorptiometry every 6 months. PATIENTS: The subjects were 32 Japanese male patients with untreated primary osteoporosis. RESULTS: In group A, but not in group B, BMD was significantly increased at the lumbar spine both at 6 months and 12 months, and at the femoral neck at 12 months, compared with baseline. Likewise, in group A, but not in group B, both BAP and NTx were significantly decreased at all time points measured (3 months, 6 months, and 12 months), compared with baseline. CONCLUSION: These results confirmed the beneficial effects of risedronate upon increasing BMD and reducing bone turnover markers in Japanese male patients with primary osteoporosis, comparable to those previously reported in postmenopausal patients with osteoporosis.

Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene (RLX) improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure how to monitor the therapeutic effects of RLX, while numerous clinical trials for other antiresorptive agents have suggested that greater short-term reductions of bone turnover markers (BTMs) can predict greater increases in BMD and greater reduction in risk of future fractures. The purpose of this study was to investigate associations between short-term reductions of BTMs and subsequent changes of BMD after 1-year treatment with RLX. Seventy-three Japanese postmenopausal women with untreated osteoporosis were selected for this study. Reductions in BTMs [bone-specific alkaline phosphatase (BAP) or serum N-terminal telopeptide of type I collagen (NTx)] after 3 months did not correlate with increases of BMD at any major sites (lumbar spine, femoral neck, total neck, and distal 1/3 radius) either after 6 months or after 12 months. Our results suggest that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict increases of BMD. However, this does not directly mean that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict risk reduction of future fractures or the ultimate effects of RLX on bone. Further studies with fracture endpoints in longer observation and larger number of patients are warranted to establish how to monitor the therapeutic effects of RLX or early identification of responders or nonresponders to RLX treatment.

Association between baseline values of bone turnover markers and bone mineral density and their response to raloxifene treatment in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure which patients are more likely to respond to treatment with raloxifene in patients with postmenopausal osteoporosis. The purpose of this study was to investigate associations between baseline values of BMD and bone turnover markers (BTMs) and changes of those values after 1-year treatment with raloxifene. Sixty-eight Japanese postmenopausal women with untreated osteoporosis were selected for this study, among whom 58 patients (mean age 70.40 +/- 9.2 years) completed this study. Lower baseline values of BMD at the lumbar spine, the femoral neck, and the distal radius were significantly correlated with greater increases of BMD at those corresponding sites after 1-year treatment with raloxifene. On the other hand, higher baseline values of bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) were significantly correlated with greater reductions of BAP and NTx, respectively, after 1-year treatment with raloxifene. Although longer and larger studies with fracture endpoints are needed, our findings suggest that baseline values of BMD and BTMs can be used to predict subsequent skeletal response to raloxifene therapy in Japanese postmenopausal women with osteoporosis.

Increased bone turnover in patients with hypercholesterolemia.

Osteoporosis has been linked with arteriosclerotic vascular diseases, suggesting that hypercholesterolemia or dyslipidemia may be a common pathogenetic factor underlying these diseases. However, little is known about the relationship between osteoporosis and hypercholesterolemia. The purpose of this study was, therefore, to investigate the effects of hypercholesterolemia upon bone metabolism, by measuring bone turnover markers in hypercholesterolemic patients. This study included 281 Japanese patients with hypercholesterolemia, and 267 control subjects. Serum bone-specific alkaline phosphatase (BAP) of the patients was significantly higher than that of the controls in women. Serum N-terminal telopeptide of type I collagen (NTx) of the patients was significantly higher than that of the controls in both men and women. In addition, both BAP and NTx in men showed a significantly negative correlation with high density lipoprotein cholesterol (HDL-C). On the other hand, in women, both BAP and NTx showed a significantly positive correlation with total cholesterol and low density lipoprotein cholesterol (LDL-C). These results indicate increased bone turnover in hypercholesterolemic or dyslipidemic patients regardless of gender, and suggest the importance of treating hypercholesterolemia or dyslipidemia in order to prevent not only arteriosclerotic complications but also osteoporotic bone loss and subsequent fractures.

Efficacy of combined treatment with raloxifene and alfacalcidol on bone density and biochemical markers of bone turnover in postmenopausal osteoporosis.

Because both raloxifene (RLX) and alfacalcidol (ALF) have been established as therapeutic agents for osteoporosis, it is tempting to speculate that the combination therapy of RLX and ALF might provide benefits over that of either one alone. However, the efficacy of the combination therapy has not been reported yet. The purpose of this study was thus to assess the efficacy of the combination therapy on bone mineral density (BMD) and bone turnover in patients with postmenopausal osteoporosis. Sixty postmenopausal patients (mean age 71.62 +/- 9.9 years) with untreated osteoporosis were selected for this study, and were randomly divided into two groups by therapeutic regimen. Group A consisted of 28 patients treated with RLX plus ALF, while Group B consisted of 32 patients with RLX alone. Among them, 20 in group A and 22 in group B completed this study. Contrary to our expectations, at either 6 months or 12 months after the initiation of treatment, RLX plus ALF did not increase BMD at any of the skeletal sites measured, including lumbar spine, femur, and radius, nor did it reduce bone-specific alkaline phosphatase or N-terminal telopeptide of type I collagen more than RLX alone. Our results do not support the hypothesis that the combination therapy of RLX and ALF exerts more beneficial effects on bone compared than with RLX alone. However, it still remains unclear from this study whether the combination therapy of RLX and ALF is more efficacious in preventing fractures compared with RLX alone. Further studies are needed to clarify these issues.

[Parathyroid and bone. Medical management of primary hyperparathyroidism].

Although the role of medical management for primary hyperparathyroidism (PHPT) is still controversial, there are subsets of symptomatic patients with PHPT who may benefit from medical rather than surgical treatments. Estrogen remains an excellent option for selected postmenopausal women. Bisphophonates may be useful to provide skeletal protection and to treat osteoporosis associated with PHPT.

Short-term effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia.

OBJECT: No consensus has been reached whether clinical use of statins has beneficial effects on bone health, partly due to lower statin concentrations because of first-pass metabolism by the liver. We thus evaluated the effects of pitavastatin, which does not undergo first-pass metabolism, on bone metabolism. METHODS: According to the therapeutic regimen, the subjects were divided into two groups (group A, 66 with pitavastatin; group B, 35 without pitavastatin). Bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) as bone turnover markers (BTMs) were compared between the two groups and between at baseline and after 3 months of treatment in each group. Correlations between baseline characteristics and deltaBTMs, and between delta lipid profile and deltaBTMs were investigated using both Pearson's correlation analysis and multivariate analysis. PATIENTS: The subjects were 101 patients with untreated hypercholesterolemia. RESULTS: After 3 months of treatment, BAP in group A did not change significantly compared with either the baseline value or that in group B. However, NTx in group A significantly decreased compared with both the baseline value and that in group B. In addition, deltaNTx was negatively correlated with NTx at baseline, and the significance of this correlation persisted after multiple regression analysis. CONCLUSION: Our findings suggest that pitavastatin may have potentially beneficial effects on bone metabolism primarily by reducing bone resorption rather than by stimulating bone formation. Further studies with more patients and longer duration are warranted to evaluate its effects, if any, on prevention of osteoporosis and subsequent fractures.

Clinical significance of 1-year treatment with raloxifene on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene (RLX) has beneficial effects on bone primarily in Caucasian women. However, to date, there is a dearth of data for Japanese postmenopausal women. In this study, we prospectively evaluated the effects of RLX on bone and lipid metabolism in fifty Japanese postmenopausal patients with untreated osteoporosis. We measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at 7 sites including the lumbar spine, femoral neck, and distal radius. BMD was significantly increased at the lumbar spine both at 6 months and at 12 months compared with at baseline (p<0.01 for both), although the possibility could not be completely excluded that this increase may be partly explained by an apparent increase induced by degenerative changes in lumbar vertebrae since we had no control subjects to compare and be more certain of the findings in this study. Both bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) significantly decreased both at 6 months (p<0.01 for both) and at 12 months (p<0.01 for both) compared with at baseline, but not below the lower limit of the reference value. Total cholesterol and low-density lipoprotein cholesterol were significantly improved while triglycerides and high-density lipoprotein cholesterol were unaltered. Although longer and larger studies with fracture endpoints are needed to draw definite conclusions, our findings suggest the favorable effects of RLX on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis as in Caucasian women.