BOSTON—In the mid-19th century, thousands of children in England and northern Europe were marked by abnormally large heads, twisted long bones, and enlarged wrists and ankles. These children had rickets—the softening of bones that leads to bone fractures and deformities—because sunlight deprivation and their bread-and-water diets didn’t provide enough calcium and vitamin D.
Rickets is still a problem today in developing countries. But, in the U.S., bone diseases like rickets, avascular necrosis (AVN), and osteoporosis are relatively rare in children. An estimated 30% to 40% of adults over 60 have osteoporosis, and incidence increases with age. But, as C. Egla Rabinovich, MD, co-chief of pediatric rheumatology at Duke University School of Medicine in Durham, N.C., noted, pediatric osteoporosis doesn’t even have its own Wikipedia page.
Recent evidence, however, suggests that the epidemiological roots of osteoporosis and avascular necrosis lie in childhood, according to speakers at a session called “Bone Health in Children and Adolescents with Rheumatic Disease,” at the ACR/ARHP Annual Scientific Meeting in Boston last November. The three experts—Dr. Rabinovich; Matthew Warman, MD, professor of orthopedic surgery at Children’s Hospital Boston; and Julian M. Aldridge, MD, assistant professor of surgery in the division of orthopedic surgery at Duke University Medical Center—also discussed what makes healthy bones, how this process is disrupted in children with bone diseases, and the controversy surrounding treatment options for children.
What Makes Healthy Bones?
In both children and adults, bones are constantly changing. Mesenchymal stem cells (MSCs) in the bone marrow constantly produce new osteoblasts while hematopoietic stem cells (HSCs) give rise to osteoclasts that resorb the old tissue.
But the process is even more dynamic in children than in adults because their bones are growing. During childhood—and particularly in infancy and adolescence—the process of formation by osteoblasts predominates, which leads to a net increase in bone mass and size. Our peak bone mass occurs right after puberty, and usually remains stable until at least age 30. After that, bone resorption by osteoclasts happens more rapidly, gradually increasing with age.
This situation makes childhood and adolescence critical times for optimizing bone growth, acquiring calcium, and, as Dr. Rabinovich put it, is “our best window of opportunity for preventing osteoporosis.” It’s also why pediatric osteoporosis is often called a “silent” disease, because the bone fractures it causes may not show up for many decades.
The session began with an overview of bone biology in children. Dr. Warman stressed first that doctors must remember that bone growth depends on both genetic and environmental factors. The trait for height, for instance, “has been increasing about an inch a generation since the late 1800s,” he said. “Our genes have actually not changed that much since then; therefore, determination of height is clearly has a strong environmental contribution.”
Moreover, bone biology is different depending on the developmental stage. “What happens in the womb is different than what happens when you’re born, different form puberty, different from adulthood,” he said. Too much calcium prenatally, for instance, would make a fetus grow too large and ultimately harm its mother. At the same time, a fetus that doesn’t grow large enough will be at greater risk of dying once leaving the womb.
One of the most important cellular factors in keeping bones healthy is the normal development of osteoblasts. Dr. Warman noted that several studies from the past couple of years have shed light on the function of these cells.
One study investigated whether a decrease in bone mineral density (BMD) is reversible. Previous work had shown that many adult women taking depot medroxyprogesterone acetate (Depo-Provera, or DMPA)—an injectable form of contraception—also had decreased BMD. Nobody knew if this also happened in adolescents, whose bones are still accruing minerals, or, if it did, if the process would reverse itself once the DMPA was discontinued. In 2005, Delia Scholes of the Group Health Cooperative in Seattle studied just that, with a sample of 170 women aged 15 to 19. Scholes found that adolescents, too, lose a significant amount of BMD while taking DMPA, especially around the hip and spine. However, once the DMPA was discontinued, the adolescents began to regain the bone mass that they had lost. “Whether that’s at the level of mesenchymal stem cells hasn’t been answered,” said Dr. Warman. And whether being on DMPA allows a woman’s bone mass to get as high as it would have if not on it, “is also an unanswered question,” he noted.
Dr. Warman next described studies from his own lab and others’ that analyzed how stem cells differentiate into osteoblasts. The process depends on a variety of factors, including the expression of tumor necrosis factors (TNF), mononuclear phagocyte colony-stimulating factors (M-CSF), lipoprotein receptors (LRP), and Wnt cell signaling.
Doctors commonly use a T-score to read the results gleaned from [children’s DEXA scans] because that’s what’s used for adults. But they should use a Z-score instead, so that the patient’s bone mass is compared to age-adjusted norms.
In elderly populations, risk factors for osteoporosis are easy to spot, including low calcium and vitamin D intake, physical inactivity, extreme thinness, excessive caffeine or alcohol intake, corticosteroid medications, and cigarette smoking. But, in children, risk factors are far more difficult to determine. Physical activity and calcium intake have been linked to higher BMDs in children, and juvenile rheumatoid arthritis, diabetes, and steroid use have been shown to put kids at increased risk.
The World Health Organization defines osteoporosis as having a BMD that is 2.5 standard deviations below that seen in a healthy normal adult. But, in children, whose BMD is continually changing as they grow, there is no accepted definition for osteoporosis. Dr. Rabinovich said that most experts believe that, in children, a fragility fracture (a fracture of trauma) plus evidence of low bone mass constitutes osteoporosis. “Unfortunately, doctors are often left with the ‘I know it I when I see it’ ” approach, she said.
What’s the best way to measure bone mass? The most commonly used tool is dual energy radiographic absorptiometry (DEXA). Though the use of DEXA has been validated in the adult population, Dr. Rabinovich said that the pediatric software for DEXA “is much more problematic.” Doctors commonly use a T-score to read the results gleaned from the imaging because that’s what’s used for adults. But they should use a Z-score instead, so that the patient’s bone mass is compared to age-adjusted norms. Dr. Rabinovich said that the mistake is all too common.
But even after you have a measure of bone density, she said, “bone density does not mean bone strength.” Bone strength also includes measures of structural properties, geometry, cortical thickness, and the material properties of collagen.
Finally, she addressed “the questions everybody wants answers to”: who to treat, when, and for how long?
Regarding pharmacological treatment, all options have had their share of controversy. Dr. Rabinovich noted that calcitriol was shown to be ineffective. Fluoride, she said, “is fascinating,” because it was shown to increase BMD but ultimately increase the rate of fractures. Parathyroid hormone (PTH) has been used in the adult population, but has not yet been tried in children. “There’s a concern of osteosarcoma risk,” she said, so doctors have been “very hesitant to give it to children.”
Finally, “that leaves us with bisphosphonates,” she said. These agents inhibit bone resorption. A study in the late 1970s showed that this therapy significantly increased BMD in children. However, because bisphosphonates slowly get released from bone, and have a half-life in bone of as much as 10 years, there is some concern about their potential long-term effects. “If girls become pregnant, will their fetuses be exposed?” she asked. Some anecdotal reports of prolonged administration, she added, found that it made bones brittle.
The best treatment strategy is to “start with the basics,” said Dr. Rabinovich. Physicians should recommend calcium supplementation, increased physical activity, and aggressively treat any inflammatory disease. The best source of calcium for children is low-fat dairy products, such as milk, cheese, and yogurt. Other foods that are rich in calcium include sardines, canned salmon, broccoli, and dark, leafy greens.
Virginia Hughes is a medical writer based in New York City.