The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

Zoledronic acid-induced hepatotoxicity relieved after subsequent infusions in a Chinese woman with glucocorticoid-induced osteoporosis.

BACKGROUND: Zoledronic acid (ZOL) is widely used for treatment of glucocorticoid-induced osteoporosis. The most common adverse effects of ZOL treatment are post-dose symptoms. ZOL-induced hepatotoxicity has very rarely been reported. CASE REPORT: Here, we described a 50-year-old Chinese woman who had vertebral fractures and severe back pain after glucocorticoid therapy for Behcet disease for 13 years. Three days after ZOL 5 mg infusion in April 2012, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) levels increased by 7.7, 4.9 and 3.0 times, respectively, compared with pre-treatment values. Liver protective agents were administered per os. Her hepatic enzyme levels returned to nearly normal range 9 days post-infusion. In the subsequent ZOL infusion with 1 year interval, serum ALT, AST and GGT levels increased slightly after the second infusion and were sustained to be normal after the third infusion. Her post-dose symptoms alleviated in the meantime. CONCLUSIONS: Hepatotoxicity due to ZOL therapy is a rare, but possible adverse effect which may be relieved after subsequent infusions.

Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis: a multicenter, randomized, double-blinded, double-dummy, positive drug-controlled clinical trial.

OBJECTIVE: To evaluate whether the efficacy and safety of menatetrenone for the treatment of osteoporosis is noninferior to alfacalcidol in Chinese postmenopausal women. METHOD: This multicenter, randomized, double-blinded, double-dummy, noninferiority, positive drug-controlled clinical trial was conducted in five Chinese sites. Eligible Chinese women with postmenopausal osteoporosis (N=236) were randomized to Group M or Group A and received menatetrenone 45 mg/day or alfacalcidol 0.5 µg/day, respectively, for 1 year. Additionally, all patients received calcium 500 mg/day. Posttreatment bone mineral density (BMD), new fracture onsets, and serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were compared with the baseline value in patients of both groups. RESULTS: A total of 213 patients (90.3%) completed the study. After 1 year of treatment, BMD among patients in Group M significantly increased from baseline by 1.2% and 2.7% at the lumbar spine and trochanter, respectively (P<0.001); and the percentage increase of BMD in Group A was 2.2% and 1.8%, respectively (P<0.001). No difference was observed between groups. There were no changes in femoral neck BMD in both groups. Two patients (1.9%, 2/108) in Group M and four patients (3.8%, 4/105) in Group A had new fracture onsets (P>0.05). In Group M, OC and ucOC decreased from baseline by 38.7% and 82.3%, respectively (P<0.001). In Group A, OC and ucOC decreased by 25.8% and 34.8%, respectively (P<0.001). Decreases in serum OC and ucOC were more obvious in Group M than in Group A (P<0.001). The safety profile of menatetrenone was similar to alfacalcidol. CONCLUSION: Menatetrenone is an effective and safe choice in the treatment of postmenopausal osteoporosis in Chinese women.

[CDC73 gene mutation and parafibromin expression status of parathyroid carcinoma in Chinese].

OBJECTIVE: To explore the clinico-genetic characteristics and protein status of parathyroid carcinoma (PC) diagnosed at Peking Union Medical College Hospital from January 1980 to December 2012. METHODS: Genomic DNA was extracted from peripheral blood lymphocytes and paraffin-embedded tissue for analysis. The mutations of CDC73 gene were detected by direct sequencing. And the expression of parafibromin in tumor tissues was evaluated by immunohistochemical analysis. RESULTS: Twenty-four PC patients were recruited. The mean ages at the diagnosis of PHPT and PC were 42.2 and 42.6 years respectively. The serum calcium at the diagnosis of PHPT was 3.78 mmol/L, serum phosphorus 0.65 mmol/L and the median increment of serum parathyroid hormone (PTH) level 20.0. The recurrent rate was 76.2% during a 5-year follow-up.Genetic analysis identified 11 mutations of CDC73 gene (45.8%), among which c.34_35 insCT, c.626_629 delAACA, c.260_261 delGA, c.570 delG, c.40 C>T and IVS3+1 G>A were novel mutation first identified in our cohort. Nine of them had germline mutations. All tissue samples from normal parathyroid displayed strong positive immunostaining of parafibromin. Complete (55%, 11/20) or partial (45%, 9/20) loss of parafibromin expression was observed in PC tissues. The age at the diagnosis of PHPT, serum calcium, serum phosphorus, PTH, alkaline phosphatase (ALP), bone involvement rate, kidney stone/calcification rate, recurrent rate, metastatic rate and immunostaining level showed no significant difference between the patients with and without CDC73 mutation. CONCLUSION: In Chinese population, CDC73 mutation and complete/partial loss of immunohistochemical staining for parafibromin occur frequently in PC. Therefore it may be useful in the subset of tumors with equivocal histological examination.

Expression of Ki-67, galectin-3, fragile histidine triad, and parafibromin in malignant and benign parathyroid tumors.

BACKGROUND: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Our study aimed to investigate the differential expression of Ki-67, galectin-3, fragile histidine triad (FHIT) gene, and parafibromin in PC, parathyroid adenoma (PA), parathyroid hyperplasia (PH), and normal parathyroid (NP) tissues; then to assess these expression values for use in differential diagnosis of malignant and benign parathyroid tumors. METHODS: Data of 15 cases with PC, 19 PAs, and 8 PHs were retrospectively analyzed for their clinical characteristics. The expression of Ki-67, galectin-3, FHIT, and parafibromin were detected via immunohistochemistry in the above-mentioned specimens and 6 NPs as control. RESULTS: Complete loss of parafibromin expression was seen in 9 of 15 (60%) carcinomas, and all normal parathyroid tissues and parathyroid benign tumors stained positive for parafibromin except for one (4%) adenoma. Galectin-3 staining was positive in 11 of 15 (73%) carcinomas, 5 of 19 (26%) adenomas, 1 of 8 (12%) hyperplasias, and 0 of 6 normal tissues. The Ki-67 proliferative index was high in 4 of 15 (27%) carcinomas, 1 of 19 (5%) adenomas, and none of the hyperplasia or normal tissues. FHIT expression did not differ appreciably among the tumor types. The combination of overexpression of galectin-3 or loss of parafibromin increased sensitivity for PC to 87%, while the specificity of both positive galectin-3 and positive Ki-67 could reach 100%. CONCLUSIONS: These data suggested that loss of parafibromin and overexpression of galectin-3 and Ki-67 might help to distinguish parathyroid carcinoma from other parathyroid tumors. And the combination of two or three of these markers might produce better sensitivity and/or specificity for the diagnosis of parathyroid carcinoma.

Osteomalacia and osteoporosis associated with primary intestinal lymphangiectasis.

Primary Intestinal lymphangiectasia (PIL) is a common cause of protein losing enteropathy (PLE). It will affect enter-hepatic circulation of lipid-soluble vitamin, and absorption of electrolytes, cause malnutrition related osteomalacia or osteoporosis. While seldom health care workers noted to assess and treat osteomalacia or osteoporosis in PIL. Here we report a related case. We found increased parathyroid hormone, decreased 25(OH)D3, low bone mineral density, which indicated that the PIL patient had osteomalacia and/or osteoporosis. Adequate calcium and vitamin D supply can relieve the condition efficaciously. We should pay attention to osteomalacia and osteoporosis in PIL patients.

Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature.

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ((99) Tc(m) -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in (99) Tc(m) -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by (99) Tc(m) -OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. (99) Tc(m) -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up.

[A case of adefovir dipivoxil induced hypophosphataemic osteomalacia and literature review].

OBJECTIVE: To investigate the clinical features and treatment protocol and prognosis for the hypophosphataemic osteomalacia related to adefovir dipivoxil. METHODS: Analysis was made upon a case of patient with chronic hepatitis B developed hypophosphataemic osteomalacia after administration of adefovir dipivoxil. Literature review was carried out to survey the global prevalence of hypophosphataemic osteomalacia after administration of adefovir dipivoxil among patients with chronic hepatitis B. RESULTS: The clinical symptoms started paralleling to the time taking adefovir dipivoxil, and alleviated after the patient withdrawn adefovir dipivoxil 10 weeks and was given phosphorus. Meanwhile, serum inorganic phosphorus recovered to normal (0.98 mmol/L), which lowest level was 0.77 mmol/L. Systematic review of the literature showed that hyperphosphaturia related to adefovir dipivoxil was dose-dependent, time-dependent and reversible. All reported cases of hypophosphataemic osteomalacia secondary to adefovir dipivoxil (10 mg/d) were from Asian population. CONCLUSIONS: Adefovir dipivoxil induced hypophosphataemic osteomalacia is rarely seen in clinical practice. Those patients with chronic hepatitis B who take adefovir dipivoxil, no matter dosages, should take periodical examinations including blood calcium and serum inorganic phosphorus to monitor whether hypophosphataemic osteomalacia occurs. Other anti-virus drugs could be used when it happens.

Benefit of infusions with ibandronate treatment in children with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare bone disease and its effective treatment is relatively deficient. We tried to assess the effects of new bisphosphonate, ibandronate on children with OI. METHODS: In this open-label, prospective, controlled study, 30 children with OI were enrolled. They received either infusions of ibandronate (2 mg) in every three months or oral calcitriol 0.25 µg daily for 24 months. All patients took 500 mg calcium plus 200 U vitamin D daily together. The endpoints were the change of annual new fracture rate (observed by case history and X ray films of spine), bone mineral density (BMD, measured by dual energy X-ray absortiometry), serum concentration of carboxy-telopeptide cross-links of type I collagen (CTX, bone resorption marker) and alkaline phosphatase (ALP, bone formation marker) during the follow-up. RESULTS: After the cyclic infusions of ibandronate, the annual new fracture rate was significantly decreased from 1.9 to 0.13 time, obviously lower than that of calcitriol group, which decreased from 1.8 to 1.0 time after the treatment (P < 0.001). The significant increase of BMD at the lumbar spine, femoral neck, trochanter, total hip was found in the group of ibandronate by 59.0%, 42.0%, 47.5% and 36.6% in time dependent manner (compared with the baseline, P < 0.001). The increase of BMD in ibandronate group was greater than that of calcitriol group (P < 0.001). The concentrations of ALP and CTX were obviously decreased in ibandronate group, and the reduction of CTX was more significant than that of ALP (P < 0.001). The tolerance of the children to ibandronate was quite well. Mild fever and muscle pain were found in 9 cases within 1 - 3 days after the first infusion of ibandronate, which could relieve after 1 - 2 days without special management. CONCLUSIONS: The benefits of cyclic infusions of ibandronate to children with OI are significant because ibandronate could significantly reduce annual bone fracture rate, increase lumbar and hip BMD, preserve vertebral morphometry of patients through inhibition of bone resorption.

[Clinical and molecular genetic analyses for a sporadic parathyroid carcinoma].

OBJECTIVE: To analyze the clinical and molecular genetic characteristics of one patient with sporadic parathyroid carcinoma (s-PC). METHODS: The clinical profile, laboratory data and paraffin-embedded tissue sample of a s-PC patient were collected at our hospital. Genomic DNA was extracted from the leukocytes of peripheral blood and paraffin-embedded tissue of this patient. All 17 exons of HRPT2 gene including the flanking regions of introns were amplified by PCR. The mutations of HRPT2 gene were analyzed by directly sequencing the amplified DNA fragments. Parafibromin encoded by HRPT2 gene was analyzed by immunohistochemistry. RESULTS: The patient was diagnosed as s-PC by the clinical presentations, laboratory examinations and typical pathologic characteristics. HRPT2 germline mutation was identified as a base mutation at codon 222 (CGA > TGA) and caused a nonsense mutation at the codon (R222X) resulting in a truncated protein. Parafibromin was completely lost while comparing the normal parathyroid tissues by immunohistochemistry. CONCLUSION: The altered expression of parafibromin caused by HRPT2 gene mutation is one of the molecular mechanisms for explaining the clinical manifestations of this patient.

Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia.

BACKGROUND: Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 (FGF-23) in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. METHODS: Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group (HP, 12 female and 7 male, mean age was 30 years), and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay. RESULTS: Mean FGF-23 concentrations were significantly higher in the HP group ((87.4 +/- 43.6) pg/ml) compared with the control group ((19.2 +/- 6.16) pg/ml; P < 0.001). In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection (7.8 pg/ml). Subsequently, serum 1,25(OH)(2) vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. CONCLUSIONS: Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.

Infusion of ibandronate once every 3 months effectively decreases bone resorption markers and increases bone mineral density in Chinese postmenopausal osteoporotic women: a 1-year study.

The efficacy and safety of intravenous ibandronate were evaluated in postmenopausal osteoporosis women in China. In this multicenter, positive drug-controlled study, 158 postmenopausal osteoporotic women were randomized to receive 2 mg ibandronate given intravenously once every 3 months or 70 mg alendronate given orally once per week. All women also received supplemental calcium (500 mg) and vitamin D (200 IU) daily. One hundred fifty-one patients completed the 1-year study. Ibandronate produced mean increases in bone mineral density (BMD) by 4.27% at the lumbar spine, 3.48% at the femoral neck, and 2.03% at the trochanter. Mean increases in BMD by 4.24% at the lumbar spine, 2.72% at the femoral neck, and 2.99% at the trochanter were observed in the alendronate group. No significant difference was found between the two groups in BMD in all sites measured. Significant decreases in serum c-telopeptide of type I collagen (CTX) and alkaline phosphatase (ALP) were found in the two groups after 1 and 3 months of treatment, respectively; these serum CTX and ALP levels were then maintained at the decreased levels throughout the study period (12 months). No changes of stature were found in the patients of the two groups. Adverse events were similar in the two groups, except more mild muscle pain was observed in the first month after infusion of ibandronate than with oral alendronate (P < 0.001). The results observed in Chinese patients may support the observation that intravenous ibandronate significantly reduced bone resorption and increased BMD with good tolerance in Chinese postmenopausal osteoporotic women. Use of intravenous ibandronate possibly could potentially improve compliance as compared with other oral bisphosphonates because it may avoid the peptic side effects of oral bisphosphonate.

Efficacy and safety of 2 g/day of strontium ranelate in Asian women with postmenopausal osteoporosis.

Strontium ranelate is a new effective anti-osteoporotic treatment having a unique mode of action, reducing bone resorption while promoting continued bone formation, with a broad range of anti-fracture efficacy at vertebral as well as peripheral sites. In Phase III studies, it has proven its early and sustained efficacy against vertebral fractures in Caucasians along with a significant increase in lumbar bone mineral density (BMD). The aim of this randomized double-blind study was to demonstrate the efficacy of strontium ranelate (2 g/day) on lumbar spine bone mineral density and the clinical and biological safety in Asian postmenopausal osteoporotic patients compared to placebo over 1 year. Three hundred and twenty-nine eligible women from mainland China, Hong Kong and Malaysia were randomized into the study. The baseline characteristics were similar in the treatment and placebo groups: mean age of 66.2+/-6.5 years, time since menopause 17.6+/-7.2 years. In the Full Analysis Set (FAS, N=302), the mean baseline lumbar L2-L4 BMD was 0.715+/-0.106 g/cm(2) in the strontium ranelate group and 0.708 +/- 0.109 g/cm2 in the placebo group. The mean baseline femoral neck BMD was 0.575+/-0.074 g/cm2 and 0.566+/-0.069 g/cm2 respectively and mean total hip BMD was 0.642+/-0.080 g/cm2 and 0.631 +/-0.088 g/cm2 respectively. The overall compliance was 91.4% in the study drug group, and 97.4% in the placebo group. After 1 year of treatment, the lumbar spine, femoral neck and total hip BMD in the treated group was significantly increased by 3-5% as compared to placebo. Strontium ranelate was well tolerated. The most frequently reported emergent adverse events were comparable in both groups (60.4% versus 60.0%), with majority of them being mild gastrointestinal disorders. There were no clinically relevant changes in laboratory tests, such as blood routine, hepatic and renal function. It is thus concluded that the effects of 2 g/day strontium ranelate on BMD and its safety profile in this cohort of postmenopausal osteoporotic Asian women were consistent with results obtained from Caucasian women in which the efficacy on the reduction in risk of fracture has been proven.

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass.

AIM: To observe the efficacy and safety of Rocaltrol (calcitriol) and/or Caltrate D (calicum carbonate plus vitamin D) in elderly Chinese women with osteopenia or osteoporosis. METHODS: One hundred fifty Chinese women aged over 65 years with osteopenia or osteoporosis from three centers were randomly divided into two groups. Seventy-six participants received Caltrate D as one pill daily; the other 74 participants received 0.25 mug Caltrate D plus Rocaltrol daily. The changes in bone mineral density (BMD) served as primary end-points. Height changes, the presence of new vertebral fractures, muscle strength and balance were evaluated. RESULTS: The following are the mean percentage changes (and SD) in BMD over 12 months: at L2-L4, 0.83+/-3.88 in the Caltrate D group and 2.84+/-4.04 in the Rocaltrol+Caltrate D group (P=0.003, by ANCOVA); at the femoral neck, 0.04+/-3.94 in the Caltrate D group and 2.01+/-5.45 in the Rocaltrol+Caltrate D group (P=0.085, by ANCOVA); and in the trochanter, 1.59+/-4.57 in the Caltrate D group and 3.76+/-6.25 in the Rocaltrol+Caltrate D group (P=0.053, by ANCOVA). The stand and maximal forward reach test (SMFRT) was significantly enhanced in both groups during the 12 months of treatment, but no significant differences were found between these two groups. No severe adverse event related to these medications occurred throughout the study. CONCLUSION: Treatment with Rocaltrol plus Caltrate D or Caltrate D for 12 months in elderly Chinese postmenopausal women effectively increased BMD at the lumbar spine. Rocaltrol plus Caltrate D was more effective at the lumbar spine than Caltrate D alone.

Treatment of hypocalcemia caused by hypoparathyroidism or pseudohypoparathyroidism with domestic-made calcitriol: a prospective and self-controlled clinical trial.

BACKGROUND: Parathyroid hormone deficiency or resistance may cause hypocalcemia with related symptoms and signs. Lifelong treatment of calcium combined with vitamin D or its metabolites is always necessary for these patients. Here we reported a prospective and open-label trial to investigate the efficacy and safety of domestic-made calcitriol in treatment of hypocalcemia caused by hypoparathyroidism or pseudohypoparathyroidism. METHODS: Twenty-four patients with confirmed hypoparathyroidism or pseudohypoparathyroidism aged (36.5 +/- 11.0) years old were studied. Among them, 16 patients had idiopathic hypoparathyroidism, 2 had pseudohypoparathyroidism and 6 had hypoparathyroidism secondary to cervical surgery. Serum calcium levels were lower than 1.88 mmol/L. Oral calcitriol was administered twice or three times with elemental calcium 1.2 g per day. All patients were followed every 4 weeks throughout the 12-week period. Dose adjustments of calcitriol were based on serum and urinary calcium levels and symptoms of hypocalcemia. RESULTS: Twenty patients were included by the end of this study. Muscular weakness, cramps, extremity paresthesia, Chovestek's sign and Trousseau's sign were relieved in 76.9%, 100%, 94.4%, 93.3% and 78.9% of patients, respectively. Serum calcium, plasma ionized calcium and serum phosphorus levels were (1.54+/-0.25) mmol/L, (0.64+/-0.10) mmol/L and (2.00+/-0.46) mmol/L at baseline, and reached (2.20+/-0.20) mmol/L, (0.95+/-0.06) mmol/L and (1.68+/-0.25) mmol/L (P<0.01) at the 12th week of treatment, respectively. Eighty percent of patients were assessed as effective and 20% as partly effective. Three, four and eight patients had hypercalciuria at the 4th, 8th and 12th week of treatment, respectively, which were reduced by thiazide diuretics. The final dose of calcitriol was (1.09+/-0.50) microg/d. CONCLUSIONS: Calcitriol combined with calcium can be used in treatment of hypocalcemia caused by hypoparathyroidism or pseudohypoparathyroidism effectively and safely. Serum and urinary calcium levels should be monitored during the course of the therapy.

[The efficacy and safety of intravenous bisphosphonates in the treatment of primary hyperparathyroidism complicated by hypercalcemia crisis].

OBJECTIVE: To study the efficacy and adverse events of intravenous bisphosphonates in the treatment of patients of primary hyperparathyroidism (PHPT) complicated by hypercalcemia crisis. METHODS: From October 2003 to December 2007, 14 patients admitted into our hospital were diagnosed as PHPT complicated by hypercalcemia crisis, which was defined as a serum calcium concentration greater than 3.50 mmol/L. Of them, 6 cases had parathyroid adenoma, 1 had hyperplasia and 7 had parathyroid carcinoma. One of the intravenous bisphosphonates including pamidronate, ibandronate and zoledronic acid was given for 29 times in all the 14 cases. Serum calcium, parathyroid hormone, hematology, and other biochemical markers were monitored. Adverse events were recorded. RESULTS: After intravenous bisphosphonates, the serum total calcium (Ca) levels decreased from (3.85 +/- 0.50) mmol/L to (2.86 +/- 0.39) mmol/L in (1.4 +/- 0.6) days, and were kept below 3.50 mmol/L for (10.14 +/- 8.54) days. There was no significant difference of the magnitude of decrease in serum Ca levels among the patients using pamidronate, ibandronate or zoledronic acid. The change of serum Ca level was associated with the serum Ca level before treatment. The response to intravenous bisphosphonates evaluated by the decrease of serum total calcium levels was more significant in patients with parathyroid adenoma or hyperplasia than those with parathyroid carcinoma. The most common adverse event was pyrexia, which occurred 15 times (51.7%) and 75% of the pyrexia events occurred after the first infusion. Other manifestations included fatigue, flu-like symptom, myalgia, arthralgia and diarrhea with an incidence of 3.4% each (one event in the 29 times of treatment). There were 2 events (6.7%) with mild increase of serum creatinine concentration. CONCLUSION: Bisphosphonates can decrease serum total calcium levels in hypercalcemia crisis caused by PHPT effectively with mild adverse events.

[Bone loss is more severe in younger Cushing's syndrome women than in older ones: comparison of bone mineral density between Cushing's syndrome and healthy women].

OBJECTIVE: To investigate the influence of age on bone mass in Cushing's syndrome patients. METHODS: Measurement of bone mineral density (BMD) was conducted among 57 women with Cushing's syndrome (CS) and 49 healthy women. There were 14 CS women and 14 healthy women in the group aged 20 - 29; 27 CS women and 15 healthy women in the group aged 30 - 39; and 16 CS women and 20 healthy women in the group aged 40 - 49. RESULTS: Among the healthy women the peak bone mass of lumbar spine was in the group aged 30 - 39, while the peak bone mass of hip was in the group aged 20 - 29. The BMD values of the CS women were lower than those of the healthy women, especially those in lumbar spine and in Ward's triangle. The younger the CS women, the lower the BMD Z-score (for the BMD Z-score of lumbar spine P = 0.021, for the BMD Z-score of femoral neck P = 0.020, and for the BMD Z-score of Ward's triangle P = 0.026). Seventeen of the 57 (29.8%) CS women had osteoporosis, 29 (50.9%) of the 57 had osteopenia, and 15 (26.3%) had fractures. The CS women with bone fractures had lower BMD Z-score than those without fractures (for lumbar fracture P = 0.003). CONCLUSION: The BMD of CS women is lower than that of the healthy women. Bone loss is more severe in younger CS women than in older ones. CS women with low BMD are prone to have bone fracture.

Age-related bone mineral density, bone loss rate, prevalence of osteoporosis, and reference database of women at multiple centers in China.

Our study surveyed age-related bone mineral density (BMD), bone loss rate, and prevalence of osteoporosis in women at multiple research centers in China. Survey results were used to establish a BMD reference database for the diagnosis of osteoporosis in Chinese women nationwide. We used dual-energy X-ray absorptiometry bone densitometers to measure BMD at posteroanterior (PA) lumbar spine (L1-L4; n=8142) and proximal femur (n=7290) in female subjects of age 20-89 yr from Beijing, Shanghai, Guangzhou, Chengdu, Nanjing, and Jiaxing. A cubic regression-fitting model was used to describe the change of BMD with age at various skeletal sites. Peak BMD occurred between 30 and 34 yr of age for femur neck and total femur, and between 40 and 44 yr for spine and trochanter measurement sites. Young adult (YA) BMD values (mean and standard deviation [SD], calculated as the average BMD in the age range of 20-39, were 1.116+/-0.12, 0.927+/-0.12, 0.756+/-0.11, and 0.963+/-0.13 g/cm2 at PA spine, femoral neck, trochanter, and total femur, respectively. The BMD of 85-yr-old women reflected a loss of 32% at the spine and 30-35% at femur measurement sites. The prevalence of osteoporosis, defined as a BMD of

Effect of fibroblast growth factor 9 on Runx2 gene promoter activity in MC3T3-E1 and C2C12 cells.

BACKGROUND: Fibroblast growth factor 9 (FGF9), expressed in brain, kidney and developing skeletal tissues, can physiologically inhibit endochondral ossification; but little is known about how FGF9 affects osteoblasts and its detailed regulatory mechanism. Here we examined the effect of FGF9 on the activity of the murine Runt-related transcription factor 2 (Runx2) gene promoter in preosteoblast MC3T3-E1 and premyoblast C2C12 cells. METHODS: Plasmids containing the Runx2 promoter region were transfected into MC3T3-E1 and C2C12 cells and stably transfected cell lines were established. The method of luciferase reporter gene activation was used to examine the effects of FGF9 on the promoter activity. RESULTS: FGF9 (10 ng/ml) increased Runx2 promoter activity in MC3T3-E1 cells. When MC3T3-E1 cells were treated with FGF9 plus the various inhibitors or activator of the intracellular signaling transducation pathways, including 10 micromol/L U0126 (the inhibitor of mitogen-activated protein kinase kinase), 10 micromol/L SB203580 (the inhibitor of p38/mitogen activated protein kinase), or 1 micromol/L C6 ceramide (an activator of mitogen activated protein kinase), the luciferase expression did not change significantly compared with that of the cells treated with FGF9 only. However, when C2C12 cells were treated with 10 ng/ml FGF9, Runx2 gene promoter activity first decreased and then increased over a period of 1 to 5 days. Among the above inhibitors, only U0126 (10 micromol/L) completely blocked the effects of FGF9 on Runx2 gene promoter activity. CONCLUSIONS: Our data showed that FGF9 can affect Runx2 gene promoter activity in MC3T3-E1 and C2C12 cells. The action of FGF9 appears to depend partly on the mitogen-activated protein kinase kinase/mitogen-activated protein kinase pathways in C2C12 cells.