Monday February 8 2010
Scan of bone affected by osteoporosis
Scientists have discovered a pill that heals brittle bones, reported the Daily Mail. It said the easily administered, once-a-day drug makes brittle bones strong again. The newspaper added that tests had been carried out on animals “but the researchers believe the treatment could one day help humans with fragile bones”.
As the newspaper pointed out, this research was carried out in mice and there are important differences in bone metabolism between mice and humans. This well-conducted study paves the way for future research into a compound called LP533401 as a potential treatment for osteoporosis, but it is too soon to herald this as a cure. The results must be replicated in humans before it is clear how this compound affects human health.
Where did the story come from?
The study was carried out by Dr Vijay K Yadav and colleagues from the Columbia University Medical Center and other medical and academic institutions in the US and India. The study was funded by grants from the US National Institutes of Health and a fellowship to one author from the International Bone and Mineral Society. The study was published in the peer-reviewed medical journal Nature Medicine.
This study explored whether osteoporosis could be treated by preventing the production of a gut-derived serotonin known to inhibit bone formation. While this drug may one day prove to be a successful treatment for osteoporosis in humans, the research was conducted in mice and the Daily Mail has been overly optimistic in heralding this as a cure after such early research.
What kind of research was this?
Serotonin is a neurotransmitter best known for its role as a chemical messenger in the brain, but it is also produced in large quantities in the stomach. The gut-derived serotonin regulates bone formation by inhibiting the growth of the early bone cells, called osteoblasts. This laboratory research in mice investigated whether osteoporosis could be treated by stopping this serotonin from being produced, thereby increasing bone formation.
The bone resorption (bone loss) characteristic of osteoporosis is currently treated with intermittent injections of parathyroid hormone (PTH) which increases bone formation. PTH must be injected and can only be used for a two-year period, so the search continues for other treatments that would be as effective but easier to use. Osteoporosis is also treated with bisphosphonates, a class of drugs that prevent bone digestion. This study did not compare the effects of the new drug with these types of treatments.
What did the research involve?
Researchers developed a compound known as LP533401, a chemical that inhibits the production of gut-derived serotonin. LP533401 is currently being tested at a dose of 100mg per kilogram of body weight for the treatment of irritable bowel syndrome. Previous studies have shown that the amount of LP533401 in the brain is negligible after being taken orally, suggesting it cannot cross the blood-brain barrier. The researchers note that this is important because brain-derived serotonin is important for healthy bone development (the opposite of gut-derived serotonin).
There were several steps to this study, with some experiments conducted in cells in culture and others conducted in living mice. In cells, LP533401 was demonstrated to inhibit the production of serotonin and there was a ‘dose-dependent’ reduction (ie the greater the dose, the greater the effect) in the levels of serotonin in the blood when mice were fed with LP533401.
Complex biochemical modelling was carried out to investigate how LP533401 interacts with other chemicals to prevent the production of gut-derived serotonin. The main animal experiments involved female mice that had had their ovaries removed (to simulate postmenopausal activity and the resulting bone resorption). The researchers investigated whether varying doses of LP533401 could prevent bone loss induced by removal of the mouse ovaries.
The researchers also investigated whether treatment with LP533401 could reverse osteopenia (the reduction in bone density that precedes osteoporosis) in mice. A group of mice had their ovaries removed and were then left untreated for two weeks. Some of these mice were then treated with LP533401 while others were given placebo, and the effects were compared four weeks later.
Another group of mice was left for six weeks after their ovaries were removed so that they developed more severe osteopenia. Some of these mice were then given LP533401 every day for six weeks and then compared with a group who were given the placebo. Further experiments were carried out to ensure that the drug was not having adverse effects on the gut.
The effects of LP533401 were also compared with those of PTH, the standard against which any new anabolic bone agent (ie bone building) should be compared.
What were the basic results?
Mice treated with LP533401, regardless of the dose, had higher bone mass (lower levels of resorption) than those not treated. The increase in bone mass was due to increases in osteoblast numbers, bone formation rate and in the levels of chemicals important for the development of healthy bone. In mice with osteopenia, LP533401 was able to increase bone formation to the degree that bone mass was normalised. Treatment of severe osteopenia saw bone mass return to normal levels.
The increase in bone mass was seen in vertebrae and in the long bones (although it did not affect bone length or width). There appeared to be no adverse effects on the gut in terms of gastric emptying or colon function. There were also no negative effects on platelets in the blood or clotting time.
LP533401 clearly had similar effects to PTH on bone recovery but at lower doses. However, a high dose of PTH was more efficient than LP533401 in the long bones, suggesting they may have different mechanisms.
How did the researchers interpret the results?
The researchers say that their results confirm that LP533401 can “rescue… ovariectomy-induced osteoporosis in mice even when given at a low dose (25mg per kilogram of body weight per day) and late after ovariectomy”. It does this without any adverse effects on blood or intestine function. They say these effects appear to be specifically due to an increase in the number of osteoblasts and the bone formation rate.
The researchers acknowledge that because of important differences between bone formation in mice and humans, their “results need to be confirmed in other species”. They suggest that drugs that can inhibit gut serotonin are potentially a new class of drugs for treating osteoporosis.
This well-conducted animal study paves the way for future research into LP533401 as a potential treatment for osteoporosis. This is early research and the researchers note that there are important differences in bone metabolism between mice and humans. As such, the study must be replicated in humans before it is clear whether this compound will affect human health. Also, it is unknown whether a low level of gut-derived serotonin might have unwanted effects in humans and this will need investigation.
Serotonin is an essential chemical messenger in both the brain and the gut, where it regulates intestinal activity. This research suggests that ingestion of a serotonin inhibitor, and subsequent inhibition of gut-derived serotonin, has no apparent adverse effects on gut health. However, there were no long-term follow-ups and most importantly this is a finding in mice only.
The study compares the new drug with PTH, the hormone that is currently used to encourage bone formation. However, the researchers did not compare it with other treatments for osteoporosis, such as bisphosphonates. These are also commonly used in humans but work differently (they prevent bone degeneration by osteoclasts but do not affect the osteoblasts that create new bone).
The Daily Mail has been overly optimistic in suggesting this may be a new cure for osteoporosis. It may one day prove to be an effective treatment, but there is a lot of research to be done before this becomes clear.