NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, March 7-29, 2000: Highlights of the Conference [*].

The National Institutes of Health organized this conference to define the factors associated with prevention, diagnosis, and treatment of osteoporosis. This is only the second Consensus Conference on Osteoporosis in approximately 16 years. National and international experts gathered at the conference to present the latest research findings. An independent, nonfederal, 13-member consensus panel, chaired by Anne Klibanski, MD, Harvard Medical School, was charged with addressing five questions. The panel represented the fields of internal medicine, family and community medicine, endocrinology, epidemiology, orthopedic surgery, gerontology, rheumatology, obstetrics and gynecology, preventive medicine, and cell biology. Thirty-two experts from these various fields presented data to the panel and an audience of 699. After weighing all the scientific evidence a statement was presented to the audience addressing the following five key questions:

1. What is Osteoporosis and What Are Its Consequences?

Definition

* Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength that increases the risk of fracture. The bone strength primarily reflects the integration of bone density and quality. Bone density is expressed as grams of mineral per area or volume, and bone quality is defined as the architecture, turnover, damage accumulation and mineralization. When a failure-inducing force, such as trauma, is applied to an osteoporotic bone, a fracture occurs, thus, osteoporosis is a significant risk factor for fracture.

* Primary osteoporosis can occur in both sexes at all ages, but often follows menopause in women while occurring later in life in men. Secondary osteoporosis is a result of medications, other conditions, or diseases.

* Osteoporosis is often, but not always, due to bone loss--or may occur after the menopause or as part of the aging process. It also may occur when the individual does not reach the optimal (peak) bone mass during adolescence.

Diagnosis

* There is at present no accurate measure of bone strength. Bone mineral density (BMD) is a surrogate measure accounting for about 70% of the bone strength.

* The World Health Organization (WHO) has defined osteoporosis as a bone density 2.5 SDs below the mean for young adult women.

Implications

* Mortality and morbidity following hip fractures are significant. Within one year of a hip fracture, one in five patients dies. Only one-third of patients regain their prefracture level and one-third require nursing home placement. Fear, anxiety and depression are common.

* Estimated costs for treatment of osteoporotic fractures are $10-$15 billion annually. These figures do not include indirect costs such as lost wages or productivity of the patient or caregivers.

2. How Do Risks Vary Among Different Segments of the Population?

Sex/Ethnicity

* Prevalence of osteoporosis and the incidence of fracture vary by gender and race/ethnicity. Postmenopausal white women have almost three-quarters of all hip fractures and the highest age-adjusted incidence of fracture. However, women of other ages, races and ethnicities are also affected, as well as men and children.

* Both men and women have an age-related decline in BMD beginning in midlife. While women experience more rapid bone loss in the early years after menopause, hypogonadism is an important risk factor in men. Men and perimenopausal women with osteoporosis are more likely to have secondary causes for the bone loss than do postmenopausal women.

* African American women have a higher BMD than Mexican American women, who have a higher BMD than white non-Hispanic women. Native American women have lower BMDs than white non-Hispanic women.

Risk Factors

* Predictors of low bone mass include female sex, increased age, estrogen deficiency, white race, low weight and body mass index (BMI), and family history of prior fracture.

* Fracture risk has been associated with a history of falls, low physical function such as slow gait speed and decreased quadriceps strength, impaired cognition, impaired vision, and the presence of environmental hazards.

* The risk of a fracture occurring in a fall increases in tall people and in falls to the side, and may be influenced by attributes of bone geometry such as hip axis and femur length.

* Models of risk prediction have been developed which incorporate clinical risk factors along with BMD measurements.

Secondary Osteoporosis

* About 30% to 60% of osteoporosis cases in men are associated with secondary causes. The most common causes are hypogonadism, use of glucocorticoids and alcoholism. About 50% of the cases in women are related to secondary causes. The most common causes include hypoestrogenemia, use of glucocorticoids, thyroid hormone excess and anticonvulsant therapy. Premature and low-birthweight infants have lower-than-expected bone mass in the first few months of life, however, the long-term implications are not known.

Children and Adolescents

* Cystic fibrosis, celiac disease, and inflammatory bowel disease are associated with malabsorption and resultant osteopenia in some people.

* Hypogonadal states, characterized clinically by delayed menarche, oligomenorrhea, or amenorrhea, are somewhat common in adolescent girls and young women. These occur with strenuous athletic training, emotional stress, and low body weight.

* Anorexia nervosa and other nutrition-related factors are critical as evidenced, in part, by the failure of estrogen replacement to correct the bone loss.

Residents of Long-term Care Facilities

* Residents of nursing homes and other long-term care facilities also have a high risk of fracture because most of them have low BMD and a high prevalence of other risk factors.

3. What Factors Are Involved in Building and Maintaining Skeletal Health Throughout Life?

* Bone accumulation is not completed until the third decade of life, after the cessation of linear growth.

* The bone mass attained early in life may be the most important determinant of skeletal health in later life.

* Genetic factors exert a strong and perhaps predominant influence on peak bone mass. Physiological, environmental, and modifiable life-style factors can also play a significant role.

* Maximizing bone mass early in life offers a critical opportunity to reduce the impact of bone loss related to aging.

Nutrition

* Calcium is the single most important nutrient for attaining peak bone mass and for preventing and treating osteoporosis.

* Daily calcium intakes of 800 mg for children aged three to eight years and 1,300 mg for children and adolescents aged nine to 17 years are suggested by the Institute of Medicine. Only about 25% of boys and 10% of girls aged nine to 17 years meet these recommendations.

* Daily calcium intake for older adults should be maintained at 1,000 to 1,500 mg, yet only about 50%-60% of this population meet this recommendation.

* The recommended daily vitamin D intake is 400 to 600 IU for adults.

* Higher dietary protein, caffeine, phosphorus, and sodium can adversely affect calcium balance. These effects appear not to be important in individuals with adequate calcium intakes.

Exercise

* Regular resistance and high-impact exercises are likely the most beneficial types of physical activity.

* Exercise later in life, even beyond age 90 years, can increase muscle mass and strength two-fold or more in frail persons.

* Exercise in elderly people delays loss of independence and reduces the risk of falls by about 25%.

Gonadal Steroids

* Secretion of sex steroids during puberty increases BMD and peak bone mass. Gonadal steroids influence skeletal health in both men and women all through life.

* Reduction in estrogen production at menopause is the major cause of BMD loss during later life. Estrogens have also been related to the growth and maturation of the male skeleton.

Growth Hormone and Body Composition

* Growth hormone deficiency is associated with a BMD decrease. While there is a direct association between the Body Mass Index (BMI) and bone mass throughout adult years, it is not clear whether the association between body composition and bone mass is due to hormones, nutrition, higher impact during weight-bearing activities, or other factors.

* Several observational studies of fractures in older persons show an inverse relationship between fracture rates and BMI.

4. What Is the Optimal Evaluation and Treatment of Osteoporosis and Fractures?

Goals

* Establish the diagnosis of osteoporosis on the basis of assessment of bone mass.

* Establish the fracture risk.

* Determine the need for instituting therapy.

Methods

* History taking and a physical examination are essential in evaluating fracture risks and should include assessment for loss of height and change in posture.

* Laboratory evaluation for secondary causes of osteoporosis should also be considered when osteoporosis is diagnosed.

* Measurements of BMD made at the hip predict hip fracture better than measurements made at other sites. BMD measurement at the spine predicts spine fracture better than measurements at other sites.

* Newer measures of bone strength, such as ultrasound, have been established. Studies using quantitative ultrasound (QUS) of the heel have predicted hip fracture and all nonvertebral fractures nearly as well as dual-energy x-ray absorptiometry (DXA) at the femoral neck. Quantitative ultrasound and DXA at the femoral neck offer independent information about fracture risk. Both of these tests predict hip fracture risk better than DXA at the lumbar spine.

* Bone strength is also affected by the rate of remodeling that can be assessed by the measurement of surrogate markers of bone turnover in the blood or urine.

* According to available data, marker levels do not predict bone mass or fracture risk. They are only weakly associated with changes in bone mass, and therefore are of limited use.

The Role of Screening

* The value of universal screening, especially in perimenopausal women, has not been established.

* Until there is good evidence to support the cost-effectiveness of routine screening, or the effectiveness of early initiation of preventive drugs, an individualized approach is recommended.

Effective Medical Treatments

* Calcium and vitamin D intake modulates age-related increases in parathyroid hormone levels and bone resorption. The optimal daily effective dose of vitamin D is uncertain, but thought to be 400-1,000 IU. The preferred source of calcium is dietary. Calcium supplements need to be absorbable and have United States Pharmacopeia designation.

* Physical activity is necessary for bone acquisition and maintenance throughout adulthood. High-impact exercise, such as weight training, stimulates accrual of bone mineral content in the skeleton. Lower-impact exercises, such as walking, have beneficial effects on other aspects of health and function, although their effects on BMD have proved minimal.

* Cyclic etidronate, alendronate, and risedronate increase BMD at the spine and hip in a dose-dependent manner and reduce the risk of vertebral fractures by 30%-50%, and reduce the risk of subsequent nonvertebral fractures in women with osteoporosis and adults with glucocorticoid-induced osteoporosis. The safety and effectiveness of this therapy in children and young adults has not been evaluated.

* Hormone replacement therapy (HRT) has shown significant efficacy in studies with BMD as the primary outcome. However, there is a paucity of trials with fractures as the end point.

* Selective estrogen-receptor modulators (SERMs), such as raloxifene, have reduced the risks of vertebral fracture by 36%.

* Natural estrogens, especially plant-derived phytoestrogens, have shown no reduction in risk of fracture in humans.

* Salmon calcitonin has had positive effects on BMD at the lumbar spine. A significant reduction in vertebral fracture risk was observed at the 200 IU daily dose, but not at the 100 IU or 400 IU daily doses.

* Nonpharmacological interventions aimed at preventing falls and reducing their effect on fractures are promising. These interventions have included hip protectors and multifactorial approaches to prevent falls.

Monitoring Treatment Response

* Goals of monitoring treatment are to increase adherence to treatment regimens and determine responses to treatment.

* Monitoring by densitometry or measurements of bone markers have not been effective in improving compliance, and further research is needed.

* The best tests for monitoring treatment response would show the largest changes with the least error and regression to the mean.

* Physicians should not stop or change therapies with demonstrated efficacy solely because of modest loss of bone density or adverse trends in markers of bone turnover.

Orthopedic Management of Osteoporotic Fractures

* Proximal femur (hip) fractures comprise about 20% of all osteoporotic fractures.

* One-year mortality rate following hip fracture is about one in five.

* As many as two thirds of patients with hip fractures never regain their preoperative activity status.

* Adverse effects of vertebral fractures on health, function, and quality of life are often underestimated.

* The occurrence of a single vertebral fracture substantially increases the likelihood of future fractures and progressive kyphotic deformity.

* Open surgical management is reserved only for those rare cases involving neurologic deficits or an unstable spine.

* Vertebroplasty and kyphoplasty involve the injection of polymethylmethacrylate bone cement into the fractured vertebra. Neither technique has been subjected to controlled trials to demonstrate the benefits over traditional medical management.

* Management during the perifracture period should consider blood clot prevention, the avoidance of substances that may inhibit fracture repair and the frequent need for supplemental caloric intake.

* More aggressive diagnostic and therapeutic intervention in this population represents an opportunity to prevent subsequent fractures. Physicians treating the acute fracture should initiate an osteoporosis evaluation and develop a treatment program or should refer the patient for an osteoporosis assessment.

5. What Are the Directions for Future Research?

The following questions, issues and concerns need addressing:

* Strategies to maximize peak bone mass in girls and boys.

* Further research regarding the risks for fracture in chronic diseases affecting children.

* Pharmacogenetic approaches for identifying and targeting specific genetic factors predisposing to osteoporosis.

* Further research on the use of bisphosphonates or other agents in young adults with secondary osteoporosis.

* A comprehensive evaluation of a validated risk assessment tool.

* An algorithm that incorporates risk factors for fracture in addition to assessment of bone density.

* An evaluation of combination therapy that includes pharmacological, dietary and lifestyle interventions (including muscle strengthening, balance training, management of multiple drug use, smoking cessation, psychological counseling, and dietary interventions).

* Development of glucocorticoids with fewer adverse effects on the skeleton.

* Identification of patients for diagnosis and treatment.

* The causes of the disease in perimenopausal women.

* Research that characterizes and validates quality-of-life tools in patients across sex, age, and race/ethnicity categories.

* Data that determine which asymptomatic patients should have screening bone-density tests or when screening is justified.

* A possible connection between medications used to treat psychiatric or neurologic disorders and osteoporosis.

* Long-term consequences of osteoporosis and clinical fractures on nonskeletal body systems.

* Development and assessment of anabolic agents that stimulate bone formation.

* Accessibility to treatment.

* The most effective method of educating health care professions and the public.

* Improved reporting of BMD and fracture risk.

* Trials of dietary supplements.

* The cost-effectiveness of programs encouraging bone health.

* The influence of nutrition on micronutrients and nonpatentable medical interventions.

* The long-term effects of fractures on health, function, and quality of life.

(*.) The full text of this NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy has been published in JAMA 2001; 285:785-795. A list of the members of the Consensus Conference Panel appears at the end of the article. A listing of speakers and conference sponsors appears on the Consensus Development Program Web site at http://consensus.nih.gov.

This NIH Consensus Statement, State of the Science Statements, and related materials are available from the NIH Consensus Program Information Center, P0 Box 2577, Kensington, MD 20891; [phone]; or the NIH Consensus Development Program home page at http://consensus.nih.gov.