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A TALE OF TWO STUDIES

In Europe and Latin America, researchers seek information to convince governments to make osteoporosis a priority

(c) IOF 2005
January, 2005

Near the end of the workday, at Strangeways Research Laboratory of the University of Cambridge in England, Dr. Jonathan Reeve phones a collaborator in Warsaw, Poland.

Reeve is the coordinator of the European Prospective Osteoporosis Study (EPOS), and the two researchers have ironed out details of how the Polish researcher will ship blood samples to Strangeways for DNA extraction. Other researchers will then try to determine whether minute variations in the genetic code make some people more likely to suffer osteoporotic bone fractures.

Meanwhile, half a world and several time zones away, Dr. Patricia Clark observes as a medical student interviews an elderly woman at the kitchen table of her home in Vitória, in the Brazilian state of Espirito Santo. The serious young man, dressed in a white lab coat, asks respectfully about her diet, whether she has ever smoked, whether there is a family history of hip fractures or other indicators of osteoporosis.

Medical student Rodolfo Rozindo Machado interviews a LAVOS study participant in Vitória, state of Espirito Santo, Brazil, as study coordinator Dr. Patricia Clark (r) observes.

Medical students Rodolfo Rozindo Machado and Maria Carolina Cunha Pinheiro canvas for volunteers for the LAVOS study in Vitória, state of Espirito Santo, Brazil.

Clark is a researcher at the Centro Medico Nacional (CMN) Siglo XXI, Instituto Mexicano del Seguro Social, and Universidad Nacional Autonoma de Mexico in Mexico City. She coordinates the Latin American Vertebral Osteoporosis Study (LAVOS), and she is visiting the city of Vitória to confer with her colleagues on the Brazilian portion of the study. LAVOS is what EPOS was some fifteen years ago-an attempt to get an accurate estimate of osteoporosis rates in different countries.

Reeve is at the epicenter of what is now a complex and well-funded study, while Clark is a pioneer, trying to build something similar from scratch, but their daily challenges are not so different-Is data collection proceeding as planned? Are appropriate methods being used so that data from different countries can be compared? Will the work be done before the funding runs out?

The two researchers have something else in common-both are devoted to fighting the "silent killer," osteoporosis.

Osteoporosis – The Silent Killer

In 1969, several decades before EPOS was even a gleam in the eyes of European researchers, a middle-aged Englishwoman-Anne Glossop-was rushed to the hospital with extreme pain in her neck. X-rays showed that she had, not one, but three fractured vertebrae. Doctors suspected that she had developed osteoporosis, though three decades ago, long before the disease was given a clinical definition by the World Health Organization, it was considered a disease only of elderly women.

How could this suddenly have happened to a woman at the relatively young age of 55? The answer, of course, is that it didn't happen suddenly. Back in 1956, when Glossup was only 42 years old, she had bent down in the kitchen and been unable to straighten up.

"The pain was severe at the time but it gradually eased. I was X-rayed and treated for some years as having osteoarthritis, but the drugs had little effect," says Glossop.

By 1984, however, Glossop had suffered a series of fractures called a "fracture cascade" and it was clear that she had osteoporosis. At the same time, researchers had made some strides in understanding the disease, and they were able to prescribe calcium and hormone replacement therapy to give her bones a fighting chance.

Despite physical limitations caused by her osteoporosis, Anne Glossop has been an enthusiastic volunteer with the National Osteoporosis Society, UK.

Only in recent years has Glossop had a chance to use more advanced medications to help build bone. She has also benefited from exercise, which epidemiological studies like EPOS have shown to strengthen bones and build muscle strength and balance.

"I have almost an obsession to keep active, because I find mobility eases pain and stiffness and, even if I'm somewhat limited, keeps me in circulation," says Glossop.

But these therapies, not to mention current preventive measures, are clearly not enough. "However far we've come in the past several decades, we need to put more effort and funding into epidemiological research that can tell us why some people develop osteoporosis at a very early age, while others do so later in life or not at all," says Reeve.

17 Thousand Served, and Still Going Strong

By any measure, EPOS is a highly successful scientific endeavor. Initially called the European Vertebral Osteoporois Study (EVOS), the study was launched in 1989 to survey the incidence of vertebral fractures in a number of European countries. Once the initial survey was completed, the study was redesigned to follow up on these subjects in the future, thus becoming the European Prospective Osteoporosis Study, funded by the International Osteoporosis Foundation (IOF) and other sources.

To date, EVOS/EPOS has recruited over 17,000 subjects, men and women, aged 50-79 from 39 centres in 17 countries. More than 100 scientific articles have been published with data from the study.

Among the most recent contributions of EVOS/EPOS were two eagerly anticipated presentations at the IOF World Congress on Osteoporosis, held May 12 to 18, 2004, in Rio de Janeiro, Brazil. Researchers combined EVOS/EPOS data with those of other studies in order to perform "meta-analyses" that confirmed smoking as a risk factor for osteoporosis and also confirmed the value of measuring bone density as a predictor of fracture risk.

A current focus for EPOS coordinator Reeve is the sharing of EPOS data with the European Union-sponsored GENEMOS study on the genetics of osteoporosis. "Until recently, scientists have mainly looked for genes that affect bone mineral density, but this hasn't been very fruitful. Now the focus is on large studies of genes related directly to fracture risk," says Reeve.

GENOMOS researchers have already found one-a gene that affects oestrogen-and other genes that appear likely to affect bone strength will be examined for links to fracture. EPOS data are also being used for the NEMO Thematic Network on Male Osteoporosis, also funded in part by IOF.

A World Away, Latin America Anticipates an Osteoporosis Epidemic

"Latin America will experience the greatest surge in osteoporosis fractures in coming years compared to other regions," predicts Dr. Rubem Lederman, president of the Brazilian Osteoporosis Society and Board member of the IOF.

Currently, one of every four hip fractures in the world occurs in Latin America and Asia. As people in these regions live longer, with more sedentary urban lives, that number will increase to one out of every two fractures worldwide by 2050, according to one estimate.

And stories like that of Sergio Barrientos Arellano of Mexico will become more common.


Sergio Barrientos Arellano, Mexico

"When I was 42, I started feeling pain in one arm. I had to sleep sitting up because it hurt too much too lie down," says Barrientos. Doctors suspected that he had arthritis or even was about to have a stroke. Barrientos himself thought he had cancer, his bones ached so much."

Neither chiropractors nor regular injections of pain killers had any lasting effect, and there were periods when he couldn't keep up with his work as a bus driver and mechanic. Only when his mother-in-law went to a clinic for a bone density scan did it occur to Barrientos that he should do the same.

"The scan showed I had osteoporosis," says Barrientos. "The doctor told me I had the bones of a 60-year-old and that they were so fragile they could break.

"This is why osteoporosis is aptly called 'the silent killer,' says Dr. Jose Zanchetta, of the Instituto de Investigaciones Metabolicas in Buenos Aries and IOF Board member from Argentina. "For many people, the first sign that they have the disease could be a broken bone. If that happens to be a hip fracture, the unfortunate fact is that the patient has a high risk of death, especially in the first six months after fracture."

LAVOS-Science on a Shoestring

Latin Americans are known for their spontaneity, and the genesis of the LAVOS study was a quintessentially Latin American moment. Dr. Margarita Deleze, a colleague of Patricia Clark's from the Osteoporosis Clinic in Mexico City, was chatting with other researchers at an IOF regional meeting in Santiago, Chile in 2001. As she shared the news of a grant that Clark had just received to survey vertebral fractures in Mexico City, she suddenly had an idea.

"Margarita came back to Mexico and told me, 'I just invited everyone to join us!'" says Clark. The idea Deleze proposed was to create a multi-center study in different Latin American countries. Clark then realized that it would make sense to emulate the methods of the original EVOS survey. "Using consistent methodologies means that results from all over the world can be compared," says Clark.

The work has already begun to pay dividends. At the World Congress on Osteoporosis, data from two of the LAVOS countries were presented. Clark and her colleagues found that 19.5 percent of the women in the Mexican sample had suffered vertebral fractures, and that the rate increased exponentially with age. This overall rate is comparable to that found in some European countries, but higher than rates detected in Beijing, China or in American women of African descent.

Also from the LAVOS study, Dr. Sergio Ragi and colleagues from the Centro de Diagnóstico e Pesquisa da Osteoporose do Espírito Santo, located in Vitória, Brazil, filled a prominent gap in Brazilian public health data when they reported that 33.6 percent of the women in their survey suffer from osteoporosis.


Dr. Sergio Ragi, director of the LAVOS Brazil study, reviews bone density scans.

Ragi admits to being surprised that the osteoporosis incidence in Brazil matches that reported in North America and Europe, given Brazil's diverse ethnic admixture (accurately represented in the study population) and exposure to sun. Sun is a key source of vitamin D, a critical element that ensures that calcium forms bones.

Ragi admits to being surprised that the osteoporosis incidence in Brazil matches that reported in North America and Europe, given Brazil's diverse ethnic admixture (accurately represented in the study population) and exposure to sun. Sun is a key source of vitamin D, a critical element that ensures that calcium forms bones.

"These data reinforce the idea that Brazilian health authorities and health care providers should look for more resources and programs to prevent osteoporosis and to make osteoporosis therapies more widely available," said Ragi.

Each of the countries that joins LAVOS will enroll 400 women, and Clark expects to finish all the data collection in 2005. "We have completed data collection in three of six countries," says Clark. "The surveys in Argentina and Colombia have recently begun and we're optimistic that the Bolivian study will soon begin."

As with EVOS/EPOS, collaborating LAVOS researchers are responsible for funding the studies within their own countries, but with Latin American economies in financial difficulty, this has proved a challenge. "We have been doing this study with drops of money, really," says Dr. Clark.

While EVOS/EPOS has been the beneficiary of substantial funding from governments and other sources in Europe, LAVOS has had only two significant donors-UC-MEXUS, a collaboration between the Mexican government and the University of California system, and IOF, which has provided money for the coordinating center.

"We have had to make up the shortfalls in funding from our governments with labor, equipment, and even resources donated by the researchers," says Zanchetta, who is one of the principal investigators the LAVOS Argentina study.

The success of a multinational Latin American study like LAVOS could have significant implications for determining whether governments and other organizations support osteoporosis, according to the researchers. "Individual advocates in each country will have a very difficult time convincing health authorities that there is a real problem, without the information from a supranational organization like LAVOS," says Zanchetta.

What will happen to LAVOS after the initial survey is completed?

Its future is uncertain because LAVOS may not have the financial means to become 'LAPOS,' a prospective study, as happened with EVOS. "We, and I mean the community of Latin Americans doctors will have to take responsibility for finding the means to make such studies happen, because nobody else will," says Zanchetta.

The Study Coordinators Soldier On

The news from Poland was a step in the right direction, says Jonathan Reeve, following his phone call. The remaining blood samples from that country will all be collected in the coming two weeks.

But the deadline for completing the sample has passed, and others among the 32 EPOS study centres have also not sent their blood samples to the central GENOMOS laboratory for genetic analysis. The geneticists in the GENOMOS project are waiting by to begin the analysis of the genes.

The central GENOMOS laboratory

Reeve would like to give the remaining centres the time they need to complete their work. Without their contributions, the power of the study to detect genetic risk factors for fractures drops.

"None of our options at this point are appealing-process later samples separately at a much higher expense, hold up the GENOMOS analysis even further, or exclude any samples that arrive too late," says Reeve.

He decides to make a few more phone calls and send some emails to see about the outstanding blood samples.

Back in Vitória, Brazil, Patricia Clark and Sergio Ragi leave the medical students to their work and return to Ragi's office to discuss the second part of the survey. After the interview, each study participant will visit a clinic for a bone density scan, which will reveal which women have low bone density or have already suffered 'silent' vertebral fractures. In order that bone density scans from the different LAVOS countries are evaluated with the same methods and standards, they are all be shipped to Vitória for Ragi to read.

If LAVOS could somehow find the funding to become 'LAPOS,' no one would be happier than Clark and Ragi. But even if that does not happen, the study has already had created ripples at national levels, says Clark. For example, the strength of the Mexican LAVOS data has allowed Clark and her colleagues to get funding for a study on osteoporosis in Mexican men.

Even more importantly says Clark, "We have gathered together great researchers from across Latin America, and built infrastructure, in this first collaboration, and I am confident we will continue to work together to help understand and fight osteoporosis in our countries."

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