Background The association between and vitamin D levels and fractures is uncertain. Objective To test the hypothesis that serum 25-hydroxyVitamin D (25(OH) vitamin D) levels are associated with the risk of hip fracture in community dwelling women. Design Nested case-control study. Setting 40 US clinical centers. Participants We studied 400 cases of incident hip fractures and 400 controls matched on age, race/ethnicity and date of blood draw (average follow-up time, 7.1 years). Subjects were selected from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Measurements Serum 25(OH) vitamin D was measured on baseline serum using radioimmunoassay with DiaSorin reagents and divided into quartiles. Conditional logistic regression was used to estimate the odds ratio with 95% confidence intervals (CI). Multivariable models included age, body mass index, parental and personal history of fractures, smoking, alcohol and calcium intake, geographic location and corticosteroid use. Results The mean (standard deviation, SD) 25(OH) vitamin D (nM) was lower in cases, 56.2(20.3) compared to controls, 59.7(18), p=0.007. A 25 nM (10ng/ml) decrease in 25(OH) vitamin D was associated with a 33% increased risk of hip fracture (odds ratio=1.33; 95%CI,1.06, 1.68) in multivariable models. Compared to women with 25(OH) vitamin D ≥70.7 nM (Quartile 4), the odds ratio of hip fracture was 1.71 (1.05, 2.79), 1.09 (0.70, 1.71) and 0.82 (0.51, 1.31) in women with 25(OH) vitamin D <47.5 nM, 47.5 to 60 nM, 60 to <70 nM, respectively, p trend =0.015. This association was in part mediated by a marker of bone resorption but remained statistically significant. Adjustment for falls, physical function, frailty, renal function, or sex steroid hormones had no effect on this association. Limitations No measure of bone density. Conclusion Low serum 25(OH) vitamin D concentrations are associated with a higher risk of hip fracture. Measurement of 25(OH) vitamin D may be useful in identifying women at high risk of hip fracture.

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

PTH-related protein (PTHrP) is homologous with PTH. PTH, an effective anabolic agent for treating osteoporosis, has been shown to stimulate both bone resorption by osteoclasts and bone formation by osteoblasts. We examined whether PTHrP might share anabolic properties in osteoporosis. A 3-month double-blind, prospective, placebo-controlled, randomized clinical trial was performed in 16 healthy postmenopausal women with osteoporosis. All received calcium and vitamin D, and all continued their prior hormone replacement therapy. One group also received daily sc PTHrP (6.56 microg/kg x d, or approximately 400 microg/d), and the other group received placebo injections. The PTHrP group displayed a 4.7% increase in lumbar spine bone mineral density (BMD) and also demonstrated an increase in osteoblastic bone formation, as assessed using serum osteocalcin measurements. In contrast, there was no increase in bone-specific alkaline phosphatase and collagen-1 propeptide or either of two markers of osteoclastic bone resorption, N-telopeptide, or deoxypyridinoline. One subject in the placebo group withdrew from the study, but there were no significant adverse events in the PTHrP group. PTHrP administered sc in high doses for only 3 months appears to be a potent anabolic agent, producing a 4.7% increase in lumbar spine BMD. This compares very favorably to available antiresorptive drugs for osteoporosis and is similar to the increases in BMD at this early time point reported for PTH. Despite the high doses, PTHrP was well tolerated. Larger clinical trials are required to confirm these results and fully assess the anabolic potential of PTHrP in osteoporosis.

PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism and humoral hypercalcemia of malignancy (HHM), respectively. These syndromes are similar in several important ways, but differ in several characteristic, yet unexplained, ways. Two of the unresolved questions in HHM and hyperparathyroidism involve renal physiology. 1) Why does renal proximal tubular production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] differ between the two syndromes? 2) Do distal tubular calcium responses to PTH and PTHrP differ in the two syndromes? To address these questions, we compared the two peptides, human PTH-(1-34) and PTHrP-(1-36), in a direct, head to head study using a continuous, steady state infusion of each peptide at the same dose in normal human volunteers for 46 h. We had previously described such methods as applied to PTHrP, but a direct multiday comparison of PTHrP to PTH has not previously been reported. In two groups (seven subjects each) of healthy young (25- to 35-yr-old) normal volunteers, PTH and PTHrP infused at 8 pmol/kg.h displayed similar calcemic effects, although PTH was slightly more potent in this regard. Both peptides also displayed similar phosphaturic effects. In addition, both peptides had similar effects on renal tubular calcium handling, yielding fractional calcium excretion values of approximately 3.5%, some 50% below the values (6.5%) observed in subjects rendered similarly hypercalcemic by the infusion of calcium. In contrast to these several quantitatively similar effects of PTH and PTHrP, PTH tended to be selectively more effective than PTHrP in stimulating renal production of 1,25-(OH)(2)D. These studies indicate that renal tubular calcium reabsorption is likely to contribute to hypercalcemia in patients with HHM. In addition, PTH may be selectively more effective than PTHrP in stimulating 1,25-(OH)(2)D production, in contrast to its phosphaturic, calcemic effects and its effects to stimulate nephrogenous cAMP excretion and renal tubular calcium reabsorption.

Low 25 hydroxyvitamin D (25(OH)D) levels have been linked to hip fracture in White women. To study the association of 25(OH)D to risk of fracture in multiethnic women, we performed a nested case control study within the prospective Women’s Health Initiative Observational Study. Incident fractures were identified in 381 Black, 192 Hispanic, 113 Asian and 46 American Indian women over an average of 8.6 years. A random sample of 400 White women who fractured was chosen. One control was selected per case and matched on age, race/ethnicity and blood draw date. 25(OH)D, parathyroid hormone and vitamin D binding protein (DBP) were measured in fasting baseline serum. Conditional logistic regression models were used to calculate the odds ratio (OR) and 95% Confidence Intervals (95% CI). In multivariable models, higher 25(OH)D levels as compared with levels <20ng/mL were associated with a lower risk of fracture in White women: (20-<30 ng/mL), OR=0.82; (0.59, 1.16) and (≥30.0 ng/mL), OR=0.55; (0.34, 0.89), p trend=0.02. In contrast, higher 25(OH)D (≥20 ng/mL) as compared with levels <20ng/mL were associated with a higher risk of fracture in Black women, OR=1.45; (1.06, 1.98), p trend=0.043. Higher 25(OH)D (≥30.0 ng/mL) was associated with higher fracture risk in Asian women after adjusting for DBP, OR=2.78; (0.99, 7.88), (p trend=0.04). There was no association between 25(OH)D and fracture in Hispanic or American Indian women. Our results suggest divergent associations between 25(OH)D and fracture by race/ethnicity. The optimal level of 25(OH)D for skeletal health may differ in White and Black women.

Adiponectin and leptin are adipokines that influence bone metabolism in vitro and in animal models. However, less is known about the longitudinal association of leptin and adiponectin with fracture. We tested the hypothesis that low leptin and high adiponectin levels are each individually associated with fracture risk in a prospective cohort study in Memphis and Pittsburgh, among 3,075 women and men, aged 70–79, from the Health Aging and Body Composition (Health ABC) study. There were 406 incident fractures (334 non-vertebral and 72 vertebral) over a mean of 6.5 ± 1.9 years. Cox regression was used to estimate the hazard ratios for fracture. Sex modified the association between adiponectin and fracture (p for interaction=0.025). Men with the highest adiponectin level (tertile 3) had a 94 % higher risk of fracture (HR=1.94; 95% CI 1.20, 3.16) compared to the lowest tertile (tertile 1), p for trend=0.007 after adjusting age, race, BMI, education, diabetes weight change, and hip BMD. Among women, after adjusting for age and race this association was no longer significant (p for trend=0.369). Leptin did not predict fracture risk in women (p for trend=0.544) or men (p for trend=0.118) in the multivariate models. Our results suggest that adiponectin, but not leptin, may be a novel risk factor for increased fracture risk independent of body composition and BMD and that these relationships may be influenced by sex. More research is needed to understand the physiological basis underlying these sex differences.

Osteoporotic fractures result in significant morbidity and mortality. Anabolic agents reverse the negative skeletal balance that characterizes osteoporosis by stimulating osteoblast-dependent bone formation to a greater degree than osteoclast-dependent bone resorption. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are peptide hormones which have anabolic actions when administered intermittently. The only FDA-approved anabolic bone treatment for treatment of osteoporosis in the United States is PTH 1-34, or teriparatide, administered by daily subcutaneous injections. However, PTH 1-84 is also available in Europe. Synthetic human PTHrP 1-36 and a PTHrP 1-34 analog, BA058, have also been shown to increase lumbar spine bone density. These agents and several other PTH and PTHrP analogs, including some which are not administered as injections, continue to be investigated as potential anabolic therapies for osteoporosis.

Context: PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown. Objectives:The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses. Design:This was a single-blinded, two-part, dose-escalating clinical trial. Setting:The study was conducted in a university academic setting. Patients or Other