Toshitsugu Sugimoto

BACKGROUND: Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. METHODS: Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. RESULTS: Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. CONCLUSIONS: FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

CONTEXT: Recent animal studies showed that osteocalcin action is related to not only bone metabolism but also glucose metabolism and fat mass. We investigated the relationship between two bone formation markers, serum osteocalcin and bone-specific alkaline phosphatase, and glucose metabolism, serum adiponectin, and the amount of fat mass as well as atherosclerosis parameters in men and postmenopausal women with type 2 diabetes. METHODS: A total of 179 men and 149 postmenopausal women were recruited consecutively, and radiographic and biochemical characteristics were collected. Brachial-ankle pulse wave velocity (baPWV) and intima-media thickness (IMT) were evaluated as the parameters of atherosclerosis. RESULTS: Multiple regression analysis adjusted for age, duration of diabetes, body mass index, and serum creatinine showed that osteocalcin negatively correlated with fasting plasma glucose and hemoglobin A(1c) in both men and postmenopausal women (P < 0.05) and with percent fat, baPWV, and IMT in men (P < 0.05). Osteocalcin positively correlated with total adiponectin in postmenopausal women (P < 0.001). After additional adjustments for systolic blood pressure, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, hemoglobin A(1c), and Brinkmann index, osteocalcin still significantly and negatively correlated with baPWV and IMT in men. In contrast, osteocalcin did not correlate with fasting C-peptide, and bone-specific alkaline phosphatase did not correlate with any variable in either men or postmenopausal women. CONCLUSIONS: Serum osteocalcin is associated with glucose and total adiponectin levels, fat mass, and atherosclerosis parameters in patients with type 2 diabetes, suggesting that osteocalcin is important for not only bone metabolism but also glucose and fat metabolism.

INTRODUCTION: In 1998, the first Japanese practice guidelines on osteoporosis was published. It has been updated several times, with the most recent being the full-scale 2011 edition and its abridged edition. The present guidelines provide information for the managements of primary osteoporosis in postmenopausal women and men over 50 years old, a summary of the evidence for the treatment of secondary osteoporosis, and a summary of the evidence for the prevention of osteoporosis in younger people. METHOD: The present Executive Summary is primarily based on the content of the 2011 Japanese abridged edition. One of the key changes is revision of the criteria for initiation of pharmacological treatment, along with an introduction of the fracture risk factors used in FRAX®. Key figures and tables were selected from the Japanese abridged edition and a reference list was added. RESULT AND CONCLUSIONS: The essential points of the Japanese practice guidelines on osteoporosis were translated into English for the first time. It is hoped that the content of the guidelines becomes known throughout the world.

Many clinical studies have shown that osteoporosis is associated with atherosclerosis and cardiovascular death. Although both high plasma levels of low density lipoprotein cholesterol (LDL-C) and low plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be risk factors for atherosclerosis, it is unclear whether such lipid derangements are also associated with the pathogenesis of osteoporosis. In this study, we evaluated the relationships between plasma levels of total C, LDL-C, HDL-C, or triglyceride (TG) versus bone mineral density (BMD) at the lumbar spine, femoral neck, radius, or total body as well as the presence of vertebral fractures in 214 Japanese postmenopausal women (age range, 47-86 years, mean 62.7). Multiple regression analysis was performed between BMD at each skeletal site versus each lipid level adjusted for age, years after menopause, body mass index (BMI), and %fat. Plasma LDL-C levels were significantly and inversely correlated with the absolute values of both one-third radial (1/3R) and distal radial (UDR) BMD (p<0.01), and tended to be inversely correlated with the absolute values of L-BMD (p=0.051). In contrast, plasma HDL-C levels were significantly and positively correlated with the absolute values of L, 1/3R and UDR BMD (p<0.05). On the other hand, plasma TG levels were significantly lower in women with vertebral fractures than in those without fractures (97.0+/-36.5 vs. 126.4+/-65.8 mg/dl, mean+/-SD, p<0.05). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each lipid level adjusted for age, years after menopause, BMI, and %fat as independent variables, TG alone was selected as an index affecting the presence of vertebral fractures (odds ratio: 0.51, 95% confidential interval: 0.29-0.89 per SD increase, p<0.05). Our study showed that plasma LDL-C and HDL-C levels were inversely and positively correlated with both R- and L-BMD values, respectively, while low plasma TG levels were associated with the presence of vertebral fractures in postmenopausal women. Thus, plasma lipids might be related to bone mass and bone fragility, and might be the common factor underlying both osteoporosis and atherosclerosis.