Leptin, Central Nervous System Involved in Bone Gain, Bone Loss

September 21, 2007 (Honolulu) — The discovery of a pathway in the brain that triggers osteoblast activity and the formation of bone opens the door to a new way to combat osteoporosis.

The neuromedin U pathway was described here at the American Society for Bone and Mineral Research (ASBMR) 29th Annual Meeting this week by Japanese researchers, whose work earned top honors at the meeting.

"Work by this group and other scientists has revealed a surprising finding — that bone cell activity is regulated in part by hormones and factors that are involved in the control of brain and fat metabolism," ASBMR president Steven R. Goldring, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts, told Medscape.

The work was presented by Shingo Sato, MD, from the Department of Orthopedic Surgery at Tokyo Medical and Dental University in Tokyo, Japan.

"Dr. Sato and colleagues have identified neuromedin U, a central nervous system–derived molecule that helps control appetite and fat metabolism, as a potentially important regulator of bone formation," Dr. Goldring explains.

Neuromedin U–deficient mice showed a 30% higher level of bone formation and bone mass over wild-type mice, Dr. Sato's team showed.

Leptin infusions decreased osteoblast activity in wild-type mice but significantly increased bone formation in neuromedin U-deficient mice. "However, and surprisingly, intracerebral leptin infusion paradoxically increased bone formation and osteoblast number in neuromedin U-deficient mice," Dr. Sato reported.

Earlier studies showed that the beta-blocker isoproterenol inhibits bone formation in wild type-mice. In neuromedin U-deficient mice, isoproterenol had no effect on osteoblast activity.

This discovery opens the door for a way to regulate bone formation through the leptin pathway, Dr. Sato said.

Dr. Sato's work "provides insights into the role of the nervous system in controlling bone remodeling and offers potential unique and novel approaches for preventing bone loss and treating osteoporosis," Dr. Goldring declared.

"The mission of the ASBMR, the world's largest bone research society, is the translation of the highest-quality and most recent and innovative scientific discoveries into improving the care of individuals with skeletal disorders," Dr. Goldring said as he explained why the society awarded Dr. Sato and colleagues the 2007 ASBMR Most Outstanding Abstract Award.

"Understanding the mechanisms that lead to osteoporosis is a major focus of bone research. Osteoporosis is the most common bone disease, affecting tens of millions of individuals and frequently leading to marked disability and impaired quality of life," Dr. Goldring asserted.

Neither Dr. Sato nor Dr. Goldring report any relevant financial relationships.

American Society for Bone and Mineral Research 29th Annual Meeting: Abstract 1061. Presented September 17, 2007.

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New FDA Orphan Drugs: IPI-504, Pafuramidine, Preos

September 21, 2007 — The US Food and Drug Administration (FDA) has granted orphan drug designation for IPI-504 for the treatment of gastrointestinal stromal tumors, pafuramidine for the treatment of African sleeping sickness, and PREOS for the treatment of hypoparathyroidism.

Orphan Drug IPI-504 for Gastrointestinal Stromal Tumors

On August 31, the FDA granted orphan drug designation to IPI-504 (Infinity Pharmaceuticals, Inc, and MedImmune) for the treatment of gastrointestinal stromal tumors (GISTs).

A GIST is a rare tumor that is thought to develop in the interstitial cells of Cajal (ICCs) in the wall of the gastrointestinal tract, usually in the stomach or small intestine, and can be either malignant or benign. Malignancy in the majority of cases occurs when specific mutations in the cellular signaling enzymes, KIT or PDGFRA, cause the growth and survival of the signal cell to become permanently active. Both KIT and PDGFRA are client proteins of HSP90, a molecular chaperone that responds to cell stress caused by heat.

IPI-504 is a small-molecule drug that is administered by intravenous infusion. Preclinical studies have shown IPI-504 to selectively inhibit HSP90 as well as to have broad potential to treat certain cancers when used as monotherapy or in combination with other drugs.

Orphan Drug Pafuramidine for African Sleeping Sickness

On August 31, the FDA granted orphan drug designation to pafuramidine (Immtech Pharmaceuticals, Inc) for the treatment of human African trypanosomiasis (African sleeping sickness), a parasitic infection that is transmitted to humans by tsetse fly bite.

African sleeping sickness is found in sub-Saharan Africa, with an estimated 50,000 to 70,000 people currently infected. The parasites, which multiply in subcutaneous tissues, blood, and lymph, eventually cross the blood–brain barrier to infect the central nervous system and cause systems such as confusion, sensory disturbances, poor coordination, and disturbance of the sleep cycle. The disease is fatal in patients who do not receive treatment.

Pafurmidine is the first orally administered drug for African sleeping sickness and has a favorable toxicity profile, though it is effective only during the first stage of disease — a phase that may extend over a period of years without symptoms.

Orphan Drug Recombinant Parathyroid Hormone (Preos) for Hypoparathyroidism

On September 19, NPS Pharmaceuticals, Inc, announced FDA designation of parathyroid hormone (rDNA origin) for injection (Preos) as an orphan drug for the treatment of hypoparathyroidism, a rare deficiency of parathyroid hormone.

Hypoparathyroidism can be inherited or caused by injury to the parathyroid gland and is estimated to afflict 65,000 Americans. The parathyroid hormone deficiency compromises the proper absorption of calcium, which can lead to symptoms such as tetany, hair loss, dry skin, or malformed nails; unusual sensations around the mouth and fingers; and candidiasis. Left untreated, the condition may lead to complications, including breathing problems, cataracts, and muscle, ligament, and nervous system disorders.

Recombinant human parathyroid hormone has been approved in Europe under the brand name Preotact. There is currently no FDA-approved treatment for hypoparathyroidism.

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Moderate Wine Consumption Improves Fasting Plasma Glucose Levels in Diabetics

September 21, 2007 (Amsterdam, the Netherlands) - A randomized trial conducted in diabetic teetotalers suggests that a glass of wine with dinner may improve glucose control, particularly in those with higher HbA1_c levels to begin with. The study, while small, adds to anecdotal evidence and meta-analyses that suggest wine, whose cardiovascular benefits have been widely touted, may hold specific benefits for diabetics.

Dr Iris Shai (Ben Gurion University, Beer-Sheva, Israel) presented the results of the study here at the European Association for the Study of Diabetes 2007 Meeting.

Shai noted that the proportion of alcohol abstainers is relatively high in Israel, where the study was conducted; however, the potential health benefits of moderate alcohol consumption persuaded 109 adults between the ages of 40 and 75 to participate. Indeed, dropouts during the three-month trial were higher among those randomized to the nonalcoholic diet malt beer than among those randomized to their choice of red or white wine, with many of the dropouts citing their disappointment over not being assigned to the alcohol group.

At the end of three months, 91 subjects remained in the study; those in the alcohol-intervention group experienced a statistically significant drop in fasting plasma glucose, from a mean of 139.6 mg/dL to 118 mg/dL. By contrast, subjects in the nonalcoholic-beer group experienced no real change in fasting plasma glucose.

Of note, alcohol consumption did not appear to affect two-hour postprandial glucose levels. Shai pointed out that ethanol metabolism is believed to inhibit gluconeogenesis, which could increase the risk of hypoglycemia. "Because of this, patients were guided to drink their beverage during dinner, which was a carbohydrate-based meal. But this process largely controls fasting, rather than postmeal, glycemia," she said, which might help explain the lack of an effect on two-hour postprandial glucose.

Better glucose, better sleep

Changes in fasting plasma glucose levels were particularly marked among patients who had higher baseline HbA1_c levels, Shai noted. Waist circumference and LDL levels were also reduced from baseline over the three-month period in the alcohol-intervention group, but no changes from baseline were seen in HDL levels. While "surprising," Shai suggested that the lack of effect on HDL might be due to the relatively short duration of the trial.

Prompting giggles in the audience, Shai said that despite a range of other parameters queried or measured in the trial, the only other significant difference between the two study groups was an improved ability to fall asleep, reported in the alcohol-intervention arm of the study.

Three months after the termination of the trial, 61% of the study subjects told investigators that they believed alcohol was likely beneficial and 49% were continuing to drink alcohol in moderation.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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In-House Pioglitazone Studies Support Safety, Efficacy, Yet Epidemic Rages on

September 21, 2007 (Amsterdam, the Netherlands) - Pioglitazone (Actos) manufacturer Takeda is trumpeting the results of two in-house studies presented here at the European Association for the Study of Diabetes (EASD) 2007 Meeting, with plump press packages and a media event. But the studies themselves, both poster presentations at the meeting--should not be "overinterpreted," one outside expert told heartwire.

The first study, by Teresa McCall and colleagues--with McCall and two of five coauthors being Takeda employees--found that the starting dose of 30-mg pioglitazone in the Takeda-sponsored GLAI study was better than the starting dose of 4-mg rosiglitazone (Avandia, GlaxoSmithKline) in terms of controlling glucose levels and improving lipid profiles during the three-month run-in phase of the trial.

The second study, by Dr Yaping Xu (Takeda Pharmaceuticals) and colleagues, was a retrospective analysis of the US healthcare plan database i3 Innovus. Xu et al report that risk of stroke and MI were reduced in subjects taking pioglitazone as compared with patients taking other, nonthiazolidinedione diabetes drugs.

Taken together, the findings "reinforce the consistency of pioglitazone data and underscore that Actos has different effects from the other thiazolidinedione, rosiglitazone, due to differences in molecular structure," a Takeda press release proclaims.

But commenting on the results to heartwire, Dr Giatgen A Spinas (Universitatsspital, Zurich, Switzerland) expressed misgivings about even discussing the results, saying they did not constitute "new" news and that studies of this nature cannot be used to inform the choice of drug in diabetes care.

Lipid, glucose effects of starting doses: pioglitazone vs rosiglitazone

McCall et al's analysis included 369 diabetic patients with dyslipidemia randomized to pioglitazone and 366 randomized to rosiglitazone. While the primary end point of the GLAI trial was change in triglycerides at six months, the present analysis looked only at three-month outcomes, during which time patients had not yet been uptitrated to the full dose. At this point, pioglitazone produced significantly better effects on triglycerides, HDL, non-HDL-cholesterol, and HbA1_c levels than did rosiglitazone, the authors report, suggesting that "initial treatment" with the pioglitazone starting dose is more effective than the rosiglitazone starting dose.

Spinas, however, dismissed the analysis as data mining, emphasizing that the 4-mg dose of rosiglitazone was "not a good dose," since it is already well accepted that a 4-mg starting dose is not an effective dose. Most patients need to be uptitrated to the 8-mg dose to get the benefit of rosiglitazone, he said.

"You should compare pioglitazone 30 mg with rosiglitazone 8 mg, to be fair," he said. Of note, results for the second half of the GLAI trial, looking at the maintenance doses over an additional three months, were not included in the EASD poster. Looking only at the starting doses, "this is was what you would expect; this is not new," Spinas commented. "If you really use comparable doses of pioglitazone and rosiglitazone, the effect on glucose lowering is similar and the effect on lipids is more favorable for pioglitazone, but this is not new information. We knew already about the more favorable lipid effects from the GLAI trial."

Stroke, MI: Pioglitazone vs nonthiazolidinedione drugs

Xu et al's study looked only at patients taking pioglitazone or a nonthiazolidinedione drug, using pharmacy and medical claims in the i3 Innovus database. Among the more than 11 000 patients taking pioglitazone, the relative risks of stroke and MI were lower than that of the >55 000 patients taking other diabetes drugs, even after adjustment for age, gender, hypertension, hyperlipidemia, heart failure, edema, use of concurrent antidiabetic drugs, antiplatelet drugs, and lipid-lowering drugs.

We conclude that, in a clinical-practice setting, in patients with type 2 diabetes mellitus, therapies that include pioglitazone are associated with significant reductions in the risk for stroke or MI compared with nonthiazolidinedione therapies," the authors conclude.

But again, Spinas emphasized that Xu et al's results must be firmly kept in perspective. "This is just a retrospective look at data; it may give some hints but is not proof," he said. "This can only give some hints that maybe, maybe one drug is better. But really, one should not use retrospective studies to say this. This needs to be done in a setting where patients are enrolled in a randomized, controlled, prospective study designed for this purpose."

Prevention the best medicine

That said, Spinas echoed the prediction made by others in recent months that a large, randomized study comparing pioglitazone and rosiglitazone is unlikely. "To compare the two in terms of these kinds of cardiovascular end points, stroke and MI, would take years," he said. "And in a couple of years, these drugs will not seem as fancy as they do now."

Spinas also emphasized that all the current hullabaloo over the cardiovascular safety of the thiazolidinedione class of drugs flies in the face of the fact that, particularly for rosiglitazone, red flags were raised when the agents were first approved. "We knew from the outset that there might be problems with cardiovascular disease with these drugs. This was stated from the beginning, and doctors who knew about it were probably careful about this. So this is not such a big surprise."

He believes that all of the attention being paid to the glitazone drugs and to other up-and-coming agents is diverting attention from the main problem at hand: diabetes prevention. Indeed, for all the fuss in the media and even in the cardiology community over the rosiglitazone-pioglitazone controversy, these drugs took up minimal turf in the EASD program, a nod, perhaps, to the larger task at hand.

"Diabetes is increasing, so it's going to be a market for a long time, and companies are always watching out for possible indications," Spinas observed. "But I still think the best treatment for diabetes is prevention, and we should not be treating healthy people with harmful drugs. People like to take drugs and carry on with their unhealthy lifestyles, but this should not prevent governments and society from putting the emphasis on prevention very early. There are so many drugs on the market for diabetes, but the epidemic is still increasing, and the drugs aren't helping with that."

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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Rosiglitazone and Pioglitazone: Thiazolidinedione Alert Center