By David N. Leff
As women age beyond the milestone of menopause, more than half of them suffer loss ofbone density from osteoporosis (porous bones). Bones mature to strength and high densityin early adulthood, and this determines the risk of fracture due to osteoporosis later inlife.
Worldwide each year, some 1.7 million post-menopausal women fracture a hip. this numberis expected to more than triple by the mid-21st century as more people in theindustrialized world survive to advanced age.
To prevent or mitigate osteoporosis in post-menopausal women, physicians prescribevitamin D plus calcium, along with hormones. Many of these women will be shortchanged bythe known fact that the bone disorder runs in families, driven by a genetic factor biasedagainst a significant percentage of individuals. That osteoporosis factor now turns out tobe not a multigene phenomenon, as widely assumed, but a single “central gene“that encodes the vitamin D receptor, which moves dietary calcium from gut to bone.
The current issue of Nature reports this unexpected finding from an Australianstudy titled “Prediction of bone density from vitamin D receptor alleles.“
Nigel Morrison, a molecular geneticist at the Garvan Institute of Medical Research inSydney, is the paper’s first author. “This is not going to be the only geneinvolved in bone density,“ he told BioWorld in a telephone interview.“But what’s surprising is that this single gene has a fairly strong effect.It’s a regulatory gene, in command of a lot of downstream genes,“ he said.
“Our aim is to be able to identify people at risk of osteoporosis prior to themlosing bone density through the menopause so we can target those with the greatest need ofattention,“ said Morrison.
Variant alleles account for up to 75 percent of total genetic effect on bone density inhealthy women. The Garvan group pinpointed the alleles--gene variants--in the genomes of250 normal twins, mostly of English-Irish origin. Of this cohort, 70 were identical pairsand 55 fraternal.
Restriction fragment length polymorphisms (RFLPs) found two variant alleles of thevitamin D receptor gene. These polymorphisms, which the researchers labeled Band b, werebequeathed to the twins by one of their parents.
Then Morrison and his co-workers measured bone density in their subjects’skeletons by X-ray absorption. they focused mainly on two vulnerable sites: the lumbarvertebrae in the small of the back and a bony spur at the head of the thigh-bone (femur),near where it fits into the hip.
Combining these two data points--bone density and allelic endowment--the researchersdetermined that a bb variant gene inherited from both parents correlated with high bonedensity and a BB allele with low density--hence, osteoporosis-prone. A single B or b hadsimilar but intermediate effects.
To clinch the predictive power of the discoveries, the team recruited a new cohort of311 unrelated healthy women in their 50’s and 60’s, two-thirds of thempost-menopausal. Taking the robust bone density of young women as their baseline, theresearchers looked for bone loss to a level at least two standard deviations below thatbaseline. this “fracture threshold“ would foretell the relative risk of eachallele in actually measuring likelihood of a broken bone.
In subjects with BB variant genes, they found, bone density in the lumbar spine wouldreach fracture threshold 18.4 years after onset of menopause. Those with bb genotypeswould go an additional 29 years and those with Bb, 22 years. Stated in terms of age, theaverage BB woman would reach the danger point at 65 years, the Bb women at 69, and the bbwomen at 76.
The genetic factor, Morrison said, comprises 50 percent of variations in bone density(diet, exercise and environment account for the other half). “We’ve shown thatthis vitamin-D receptor gene seems to explain about 55 percent of that geneticcomponent,“ he said.
Because of the high frequency of osteoporosis, Morrison pointed out, “it would beridiculous to say that all afflicted people were mutants or abnormal. Part of our geneticmakeup predisposes some of us to low bone density, leading to osteoporotic fracture.“
Garvan said his study, which began five years ago, is still ongoing and now numberssome 2,000 DNAs from as many individual subjects.
What sets osteoporosis apart from other genetic disorders, such as Alzheimer’sdisease, he emphasized, is that “you can do something about it. Quite effectivetherapies are available.“
“What’s good about this thing is that the gene that has a genetic effect onbone density actually produces a protein that you can manipulate,“ he continued.“You might be able to tailor the therapy according to genotype. One can easilyenvisage developing therapies based on analogs of vitamin D. So it has a great potentialfor oral therapy.“
From Research to Reality
“In the short term, the major thing is the potential in our DNA-based prognostictest for vitamin D effect in osteoporosis,“ Garvan’s executive director,molecular geneticist John Shine, who was co-founder, president and chief scientificofficer at CalBiotech (now Scios-Nova) in the 1980’s, told BioWorld. “Obviously,the institute, wanting to add value to our research, has taken out patent applications onit,“ he said. He anticipates that such a clinical test would be ready to market in acouple of years.
“In the longer term, we would certainly develop vitamin D analogs as potentialtherapeutic agents now that we’re more confident as to the targets for thedrugs,“ Shine added. “In fact, we’re beginning some work on that now.“
Garvan, he said, has entered into a range of international collaborations “to makesure findings hold up in different ethnic groups. It will be 12 to 18 months before allthat data comes in. In parallel with that, we now need to link this particular finding tosome sort of a generic DNA-type test kit, and we’re talking to a couple of differentgroups on that score.“
Biologist Joan McGowan, who heads the bone biology and disease branch at the NationalInstitute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD) stressed two thingsthat the Garvan finding does not indicate:
* “That your bone loss is predetermined and that there’s no way to influenceit.“
* “That everyone should go out and be tested for the gene, and be able tosegregate themselves in one class or another.“
Nonetheless, she said, “Garvan’s research is really at the cutting edge ofgenetic approaches to osteoporosis.“
McGowan said the Woman’s Health Initiative is gearing up to test 45,000post-menopausal women at 45 centers for vitamin D therapy and fracture as well as breastcancer and cardiovascular disease.
Asked it the Australian alleles might figure in this large-scale study, McGowanreplied, “I think there will be proposals to use some of the material generated tolook at skeletal markers, including the Garvan ones.“
NIAMSD contributed funding to the Garvan Institute’s bone study.