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Oxytocin is Lower in Osteoporotic Women


Oxytocin and bone remodelling: relationships with neuropituitary hormones, bone status and body composition.

There is growing evidence that oxytocin, which regulates appetite, plays a role in bone remodelling and improves osteoporosis. We previously showed a significant decrease in circulating oxytocin levels in postmenopausal osteoporotic women compared to healthy controls. However, factors involved in the pathophysiology of osteoporosis, such as estrogens and leptin, are known to regulate oxytocin secretion. Herein, we evaluated the relationships between oxytocin and other hormonal factors known to regulate bone remodeling and body composition in postmenopausal osteoporotic women, compared to healthy controls.
In 20 postmenopausal women with severe osteoporosis compared to 16 healthy controls, we measured serum levels of oxytocin, high sensitive estradiol, testosterone, FSH, LH, SHBG, TSH, osteocalcin, serum type I collagen carboxy-terminal telopeptide, leptin. Bone mineral density and body composition were also measured with DXA.
Osteoporotic women had significantly lower oxytocin, leptin and LH serum levels and higher CTX and SHBG; all other biological parameters were similar in both groups. Fat mass and lean mass were significantly decreased in osteoporotic women. Oxytocin serum levels were significantly correlated to bone mineral density but not to any other measured parameter, including leptin, estradiol and age. In a logistic regression analysis, osteoporosis remained significantly correlated to oxytocin, regardless of age.
Low oxytocin serum levels appeared to be associated with severe osteoporosis, independently of other factors associated with osteoporosis or known to regulate oxytocin serum levels, such as estradiol or leptin, reinforcing the concept that oxytocin may be involved in the pathophysiology of postmenopausal osteoporosis.

Breuil V, Amri EZ, Panaia-Ferrari P, Testa J…
Joint Bone Spine Dec 2011
PMID: 21441053

Oxytocin Reverses Osteopenia in Ovariectomized Mice


Oxytocin reverses ovariectomy-induced osteopenia and body fat gain.

Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor’s differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor’s differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause.

Beranger GE, Pisani DF, Castel J, Djedaini M…
Endocrinology Apr 2014
PMID: 24506069

Sclerostin Inhibitor Increases Bone Strength More than the Controls in Rats


Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.

The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin’s role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin’s role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

Li X, Ominsky MS, Warmington KS, Morony S…
J. Bone Miner. Res. Apr 2009
PMID: 19049336

Sclerostin Inhibitor Increases Bone Formation, Density, and Strength in Monkeys


Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength.

The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of I were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis.

Ominsky MS, Vlasseros F, Jolette J, Smith SY…
J. Bone Miner. Res. May 2010
PMID: 20200929

Romosozumab Phase I Trial Increased Bone Density


Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.

Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation.

Padhi D, Jang G, Stouch B, Fang L…
J. Bone Miner. Res. Jan 2011
PMID: 20593411

Blosozumab Phase 2 Trial Increased Bone Density


A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density.

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Recker RR, Benson CT, Matsumoto T, Bolognese MA…
J. Bone Miner. Res. Feb 2015
PMID: 25196993 | Free Full Text

Blosozumab: Eli Lilly’s New Sclerostin Inhibitor

Blosozumab is a new sclerostin inhibitor developed by Eli Lilly. According to Wikipedia:

Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.

Romosozumab: Amgen’s New Sclerostin Inhibitor

Romosozumab is a new Sclerostin Inhibitor from Amgen. Specifically it is a humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis. According to Wikipedia:

Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated. In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment….

The Amgen drug is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021.

Review: Sclerostin Inhibition: A New Approach


Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis.

Osteoporosis and osteoporosis-related fractures are growing problems with the aging population and are associated with significant morbidity and mortality. At this time, other than parathyroid hormone analogs, all therapies for osteoporosis are antiresorptive. Therefore, researchers have focused efforts on development of more anabolic therapies. Understanding of the Wnt signaling pathway, which is critical for skeletal development, and the role of sclerostin in inhibition of Wnt signaling has led to the discovery of a novel therapeutic approach in the treatment of osteoporosis – sclerostin inhibition. In this review, we discuss the biology of Wnt signaling and sclerostin inhibition. We then discuss human disorders of decreased sclerostin function and animal models of sclerostin inhibition. Both have served to elucidate the effects of decreased sclerostin levels and function – increased bone mass and strength and fewer fractures. In addition, we review data from Phase I and II studies of the two humanized sclerostin monoclonal antibodies, romosozumab and blosozumab, both of which have had positive effects on bone mineral density. We conclude with a discussion of the ongoing Phase III studies of romosozumab. The available data support the potential for neutralizing sclerostin monoclonal antibodies to serve as anabolic agents in the treatment of osteoporosis.

Shah AD, Shoback D, Lewiecki EM
Int J Womens Health 2015
PMID: 26082665

Calcium More or Less Than 800mg Increases Heart Risk, More or Less Than 900mg Increases All-Cause Mortality


Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies.

Considerable controversy exists regarding the association between dietary calcium intake and risk of mortality from cardiovascular disease and all causes. Therefore, we performed a meta-analysis of prospective cohort studies to examine the controversy.
We identified relevant studies by searching MEDLINE, Embase, and the Cochrane Library databases between 1 September 2013 and 30 December 2013. Reference lists of relevant articles were also reviewed. Observational prospective studies that reported relative risks and 95% confidence intervals for the association of calcium intake with cardiovascular and all-cause mortality were eligible. Study-specific relative risks were pooled using a random-effects model.
In this meta-analysis, 11 prospective studies with 12 independent cohorts, involving 757,304 participants, were eligible. There was evidence of a non-linear association between dietary calcium intake and risk of mortality from cardiovascular disease (P for non-linearity <0.01) and all causes (P for non-linearity <0.01). A dose-response analysis showed a U-shaped relationship between dietary calcium intake and cardiovascular mortality. Intakes that were lower and higher than around 800 mg/day were gradually associated with a higher risk of cardiovascular mortality. For all-cause mortality, we also observed a threshold effect at intakes around 900 mg/day. The risk of all-cause mortality did not decrease further at intakes above 900 mg/day.
This meta-analysis of prospective cohort studies suggests that dietary calcium intake is associated with cardiovascular mortality in a U-shaped manner and that high dietary calcium intake (>900 mg/day) is not associated with a decreased risk of all-cause mortality.

Wang X, Chen H, Ouyang Y, Liu J…
BMC Med 2014
PMID: 25252963 | Free Full Text

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