Cure Research for Osteoporosis


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Research list: The list of research areas and treatments under analysis mentioned in various sources for Osteoporosis includes:

  • Low-dose estrogen
  • Testosterone supplementation - though this treatment for men seems to have little effect.
  • Bisphosphonates
    • Etidronate, alendronate, risedronate
  • Selective estrogen receptor modulators (SERMs)
    • Raloxifene
  • Vitamin D metabolites
  • Parathyroid hormone
  • Sodium fluoride

Research discussion: The Study of Osteoporotic Fractures (SOF), supported by NIAMS and the National Institute on Aging (NIA) and involving more than 9,000 Caucasian women 65 years or older, described risk factors for hip, wrist, and spine fractures. The study demonstrated that bone mineral density predicts hip and other types of fractures, and also provided evidence that women with low bone density have an increased risk of stroke, as well as evidence of a relationship between bone mineral density and breast cancer incidence. The NIH Women's Health Initiative currently supports the largest study of osteoporosis and fractures ever conducted. This study will determine the usefulness of calcium and vitamin D supplements, and may lead to new public health initiatives to optimize the intake of these nutrients in the U.S. population.

While osteoporosis in women has received substantial attention, less scrutiny has been devoted to osteoporosis in men. Perhaps this is because men tend to have a higher peak bone mass at maturity and a more gradual reduction in sex hormones, resulting in a later development of osteoporosis. Yet, an estimated one-third of hip fractures worldwide occur in men. The cause and pathology of osteoporosis in men is now receiving research attention under a seven-center grant supported by NIAMS, NIA, and the National Cancer Institute (NCI). 1

Selected Scientific Advances

  • Identification of a gene essential for the formation of bone. Through a convergence of efforts by investigators around the world, research has shown that normal skeletal development--in both mice and humans--requires two active copies of the gene Cbfa1. This discovery is expected to open a number of exciting new research areas.

  • Finding that estrogen causes "programmed cell death" in cells that are responsible for degradation of bone (osteoclasts). By paving the way for future assessment of whether drugs can also affect the programmed cell death of osteoclasts (thereby making them potentially useful as bone-protecting treatments), this discovery represents an exciting link between basic research and tangible patient benefit.

  • Finding that one of a collection of molecules created by researchers (called peptidomimetics) successfully blocks part of the bone resorption process. This is the first clear indication that a particular synthetic antagonist may be effective in the prevention of osteoporosis. The finding may hold promise for combating bone loss in women who cannot tolerate estrogen.

  • Patient-based research showing that elderly women who already had several spine fractures at the start of a study experienced the greatest health benefit from calcium supplementation (both in terms of reducing the rate of new spine fractures and stopping bone loss). This finding has clear implications for developing and targeting new preventive strategies.

  • Low-dose estrogen study. Because estrogen is currently the first line of defense for osteoporosis but has known side effects, it is critical to find the lowest effective dose that will preserve and even add bone. A recent study supported by NIAMS tested the usefulness of daily low-dose estrogen plus progesterone in women over age 65 and found that these women showed significant increases in spine, forearm, and total body bone mineral density. This study provides proof that low-dose estrogen can be an effective preventive and therapeutic option.

  • Study of osteoporotic fractures (SOF). The development of risk-prediction models for osteoporotic fractures that incorporate clinical risk factors along with bone mineral density measurements is an important advance in identifying persons at greatest risk for fractures and for whom intervention measures may be suitable. The SOF, a study of postmenopausal Caucasian women, led to the identification of 14 clinical risk factors. Possession of five or more of these factors greatly increased the risk of fracture in the women in the study.

  • Secondary osteoporosis. Information regarding the diseases, physical states, medical treatments, and drugs that can lead to the development of secondary osteoporosis is now available to physicians. The information alerts physicians to the appropriate use of treatment, the monitoring of patients at risk, and, where possible, the use of intervention measures to prevent the development of osteoporosis. For example, it is generally agreed that patients on glucocorticoid therapy for 2 months or longer and patients whose conditions place them at high risk for osteoporotic fractures should be considered for bone density measurement.

  • Screening in the general population. Because there is a lack of sufficient evidence regarding the cost-effectiveness of routine screening or the efficacy of early initiation of preventive drugs, an individualized approach is recommended for testing for bone loss.

  • Testosterone study. Circulating levels of testosterone are known to decline in men as they age, leading to bone loss. A recent clinical trial of testosterone supplementation in a group of older men with low hormone levels revealed little difference in bone mineral density between the placebo- and testosterone-treated men, indicating that hormone therapy to replace bone mass is not necessary for most older men.

  • Gene for osteoporotic fractures. A recent study showed that women 65 and older with the apolipoprotein E (APOE*4) gene on chromosome 19 were nearly twice as likely as those without the gene to suffer hip and wrist fractures. Women with this gene experience weight loss that contributes to bone loss and may have reduced levels of vitamin K, which stimulates bone formation and reduces bone-cell loss.

  • Body mass index. Suboptimal bone growth in childhood and adolescence is as important as bone loss to the development of osteoporosis. Growth hormone and insulin-like growth factor-I, which are secreted the most during puberty, play a role in acquiring and maintaining bone mass and in determining body composition into adulthood. Children and youth with low body mass index (BMI) are likely to have a lower-than-average peak bone mass. There is a direct association between BMI and bone mass throughout the adult years, and several studies of fractures in older persons have shown an inverse relationship between fracture rates and BMI.

  • Nutritional studies. It is known that calcium is essential for building strong bones and reducing fracture risk. Vitamin D is required for optimal calcium absorption by the body. Both substances should be part of any osteoporosis treatment. Recent studies have shown that while some substances, such as high dietary protein, caffeine, phosphorus, and sodium, can adversely affect calcium balance, their effects appear not to be important in individuals who have an adequate calcium intake.

  • Gender/ethnicity. Caucasian postmenopausal women experience almost three-quarters of hip fractures. However, women of other age, racial, and ethnic groups, as well as men and children, are also affected by osteoporosis. Much of the difference in fracture rates among these groups appears to be explained by differences in peak bone mass and rate of bone loss. Differences in bone geometry, frequency of falls, and presence of other risk factors also appear to play a role.

  • New drugs. Bisphosphonates and selective estrogen receptor modulators (SERMs) are fairly recent prevention and treatment options for osteoporosis. Randomized placebo-controlled trials and meta-analysis of bisphosphonates (etidronate, alendronate, and risedronate) show that all increase bone mineral density at the spine and hip in a dose-dependent manner and reduce the risk of vertebral fractures by 30 to 50 percent. In large clinical trials, raloxifene, a SERM recently approved by the Food and Drug Administration, reduced the risk of vertebral fracture by 36 percent.

  • Exercise and falls. There is some evidence that childhood exercise, particularly resistance and high-impact exercise (such as weight training), contributes to higher peak bone mass. While there are health benefits to low-impact exercise, such as walking, it has minimal benefit for bone mineral density. Acknowledging that falls are a major risk factor for osteoporotic fractures, researchers conducted randomized clinical studies of exercise during adulthood and later in life that showed that the conditioning, balance-enhancing, and muscle-building effects of exercise reduce falls by approximately 25 percent.

  • Ultrasound. Clinical trials of drug therapy for osteoporosis have most often used dual photon x-ray absorptiometry (DXA) to measure bone mineral density. Studies of the less cumbersome and less expensive quantitative ultrasound (QUS) of the heel show that QUS predicts hip fracture and other nonvertebral fractures nearly as well as DXA at the femoral neck.

  • Biomarkers. Biomarkers of bone remodeling (formation and breakdown), such as alkaline phosphatase and osteocalcin (serum markers) and pyridinolines and deoxypyridinolines (urinary markers), are of limited utility in evaluating individual patients because they do not predict bone mass or fracture risk. However, research studies show that biomarkers correlate with changes in indices of bone remodeling and may provide insights into the mechanisms of bone loss.
1

In the past decade, there has been an explosion of basic and clinical research in osteoporosis. However, many fundamental advances in molecular and cellular biology, immunology, genetics, and bioengineering have not yet been applied to skeletal biology. In addition, research on SERMs holds promise for reducing bone loss in postmenopausal women without adverse effects on other organs. Vast opportunities exist to expand the current knowledge base, continuing in a diverse approach to osteoporosis. Initiatives that may serve as springboards for further research include:

  • Multicenter clinical intervention studies on combination therapies for osteoporosis. Because pharmaceutical companies tend to focus resources on bringing individual drugs to market, Federal support is needed to test combinations of drugs, as well as possible exercise and nutritional modifications to various drug combinations. Lower doses and combinations of effective agents may reduce the side effects and risks associated with current individual drug treatments, and may improve overall responsiveness. These studies will also generate information on osteoporosis in men, children, adolescents, and those who have diseases and conditions that put them at high risk for osteoporosis, moving beyond postmenopausal women, the group on whom most private sector research has been concentrated.

  • The bone density, biomarkers, and physical activity component of the National Health and Nutrition Examination Survey (NHANES) IV. National Health and Nutrition Examination Surveys have been conducted periodically since the 1960s, through household interviews and physical examinations provided in specially designed mobile examination centers, and with data collection periods ranging from 3 to 6 years. NHANES IV is planned as a continuous survey, and new data collection began in 1999. NIAMS is specifically interested in information from three tests to be included in the exam: dual photon x-ray absorptiometry (DXA), measurements of markers of bone resorption in urine and blood samples, and assessment of musculoskeletal strength in participants aged 50 and over.

  • Understanding the effects of therapeutic agents. While estrogen continues to be an important hormone for the treatment of osteoporosis, particularly in postmenopausal women, new treatment drugs have recently been introduced into the marketplace that may prove helpful to a broader population. These include alendronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator. Recent knowledge about the link between bone and the cardiovascular system suggests that drugs commonly used to reduce cholesterol may also have beneficial effects on the skeleton. NIAMS is supporting research that examines the molecular and cellular mechanisms by which currently used agents work in the hope of advancing knowledge about their application to bone.

  • Animal models to study the bone matrix. There is growing evidence suggesting that the bone matrix is a source of important biochemical signals that influence the activity of bone cells, telling them where to break down or form new bone. The identification of matrix components that influence cell function could lead to new drugs that mimic these signals. NIAMS supports research that uses new, genetically modified mice as a model to examine the interaction between bone cells and the bone matrix.

  • Control of osteoblast differentiation. Osteoblasts (bone-forming cells) arise from precursor cells that differentiate to form different tissues. Some osteoblasts differentiate further to become osteocytes, the cells that are thought to be important for the response of bone to mechanical loading. The complex balance between the generation of precursor cells, their differentiation into osteoblasts and osteocytes, and ultimately their death, determines the rate of new bone formation. NIAMS is encouraging research that addresses the control of osteoblast differentiation and the generation of genetic resources to advance this research.

  • Effect of loading on bone development early in life. Bone mass during adult life reflects the amount acquired during growth minus that which is subsequently lost. Thus, maximizing peak bone mass may provide an effective strategy to prevent osteoporosis. Two hundred prepubescent children are participating in a study to determine the impact of jumping, a high weight-bearing exercise, on the development of bone mass. The study may show that implementing a specific bone-loading program during childhood will enhance the development of both bone mass and mineralization at an earlier age. This would provide a larger foundation for mineralization and growth through adolescence, thereby reducing the risk of future osteoporotic fractures.

  • Genetic analysis of bone mass. Although lifestyle and environmental factors play a role, up to 75 percent of bone mineral density is genetically determined. Researchers are employing a new method of mapping genes that influence continuously varying traits, such as bone mass. In mouse experiments, researchers have identified 17 candidate genes that may influence the development of peak bone mass during skeletal growth. The mapping of risk and protective genes in mice and the development of unique animal models for isolating the effects of those genes offer an important route to the possible identification of risk and protective genes in humans. This would allow prediction of individual--rather than general--risk, which in turn could lead to effective targeting of prevention-based treatment strategies to high-risk populations.

  • Understanding the molecular pathways that mediate PTH. Intermittently administered parathyroid hormone (PTH) can stimulate increases in bone mass. Although practical problems may limit the use of PTH in this way, current research on the molecular pathways that mediate PTH action may make it possible to derive a similar beneficial effect in other ways.
1

Other SERMs and bisphosphonates are being studied as improved treatments for osteoporosis. Also promising as possible therapies are sodium fluoride, parathyroid hormone (PTH), and some forms of vitamin D. 2

Medical research for Osteoporosis: medical news summaries: The following medical news items are relevant to medical research for Osteoporosis:



Footnotes:
1. excerpt from Osteoporosis Progress and Promise: NIAMS
2. excerpt from Osteoporosis - Age Page - Health Information: NIA

Last revision: June 5, 2003

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