What is the optimal evaluation and treatment of osteoporosis and fractures?
The goals for the evaluation of patients at risk for osteoporosis are to establish the diagnosis of osteoporosis on the basis of assessment of bone mass, to establish the fracture risk, and to make decisions regarding the needs for instituting therapy. A history and 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 be considered when osteoporosis is diagnosed. The most commonly used measurement to diagnose osteoporosis and predict fracture risk is based on assessment of bone mineral density (BMD) which is principally determined by the mineral content of bone. BMD measurements have been shown to correlate strongly with load-bearing capacity of the hip and spine and with the risk of fracture. Several different techniques have been developed to assess BMD at multiple skeletal sites including the peripheral skeleton, hip, and spine. The World Health Organization (WHO) has selected BMD measurements to establish criteria for the diagnosis of osteoporosis. A T-score is defined as the number of standard deviations (SD) above or below the average BMD value for young healthy white women. This should be distinguished from a Z-score, which is defined as the number of SD above or below the average BMD for age- and gender-matched controls. According to the WHO definition, osteoporosis is present when the T-score is at least minus 2.5 SD. Although T-scores were based originally on assessment of BMD at the hip by dual-energy X-ray absorptiometry (DXA), they have been applied to define diagnostic thresholds at other skeletal sites and for other technologies. Experts have expressed concern that this approach may not produce comparable data between sites and techniques. Of the various sampling sites, measurements of BMD made at the hip predict hip fracture better than measurements made at other sites while BMD measurement at the spine predicts spine fracture better than measures at other sites.
Newer measures of bone strength, such as ultrasound, have been introduced. Recent prospective studies using quantitative ultrasound (QUS) of the heel have predicted hip fracture and all non-vertebral fractures nearly as well as DXA at the femoral neck. QUS and DXA at the femoral neck provide independent information about fracture risk, and both of these tests predict hip fracture risk better than DXA at the lumbar spine. In general, clinical trials of pharmacologic therapies have utilized DXA, rather than QUS, for entry criterion for studies, and there is uncertainty regarding whether the results of these trials can be generalized to patients identified by QUS to have high risk of fracture.
Over the past year, several professional organizations have been working on establishing a standard of comparability of different devices and sites for assessing fracture risk. With this approach, measurements derived from any device or site could be standardized to predict hip fracture risk. However, the values obtained from different instruments cannot be used to predict comparable levels in bone mass. Limitations in precision and low correlation among different techniques will require appropriate validation before this approach can be applied to different skeletal sites and to different age groups.
It has been suggested that the diagnosis and treatment of osteoporosis should depend on risk-based assessment rather than solely on the assessment of a T-score. Consideration of risk factors in conjunction with BMD will likely improve the ability to predict fracture risk. This approach needs to be validated in prospective studies and tested in appropriate randomized clinical trials.
In addition to the effects of bone mass, bone micro architecture, and macrogeometry, bone strength is also affected by the rate of bone remodeling. Bone remodeling can be assessed by the measurement of surrogate markers of bone turnover in the blood or urine. These markers include bone-specific alkaline phosphatase and osteocalcin, which are indices of bone formation, and the urinary levels of pyridinolines and deoxypyridinolines and serum and urine levels of type I collagen telopeptides (CTX and NTX), which are indices of bone resorption. The level of these markers may identify changes in bone remodeling within a relatively short time interval (several days to months) before changes in BMD can be detected. However, according to available data, marker levels do not predict bone mass or fracture risk and are only weakly associated with changes in bone mass. Therefore, they are of limited utility in the clinical evaluation of individual patients. Despite these limitations, markers have been shown in research studies to correlate with changes in indices of bone remodeling and may provide insights into mechanisms of bone loss.
The value of bone density in predicting fracture risk is established, and there is general consensus that bone density measurement should be considered in patients receiving glucocorticoid therapy for 2 months or more and patients with other conditions that place them at high risk for osteoporotic fracture. However, the value of universal screening, especially in perimenopausal women, has not been established. There are several unknown factors with this approach.
First, the number of women evaluated and treated would need to be high in order to prevent a single fracture. For example, in white women aged 50-59, an estimated 750BMD tests would be required to prevent just one hip or vertebral fracture over a 5-year period of treatment. Second, the value has not been established for the common practice of beginning preventive drug therapy in the perimenopausal period for the purpose of preventing fractures later in life.
Until there is good evidence to support the cost-effectiveness of routine screening, or the efficacy of early initiation of preventive drugs, an individualized approach is recommended. A bone density measurement should be considered when it will help the patient decide whether to institute treatment to prevent osteoporotic fracture. In the future, a combination of risk factor evaluation and bone density measurements mayincrease the ability to predict fracture risk and help with treatment decisions. Until assessment by randomized clinical trials is conducted, individual decisions regarding screening could be informed by the preliminary evidence that the risk for fracture increases with age, and with an increased number of additional risk factors.
- What Are the Effective Medical Treatments?
In the past 30 years, major strides have been made in the treatment of osteoporosis. Evidence-based reports systematically reviewing the data from randomized clinical trials, including meta-analyses for each of the major treatments, are available and permit conclusions regarding the role of each modality of osteoporosis therapy.
Calcium and vitamin D intake modulates age-related increases in parathyroid hormone (PTH) levels and bone resorption. Randomized clinical trials have demonstrated that adequate calcium intake from diet or supplements increase spine BMD and reduce vertebral and non-vertebral fractures. Low levels of 25-OH vitamin D are common in the aging population, and significant reductions in hip and other non-vertebral fractures have been observed in patients receiving calcium and vitamin D3 in prospective trials. The maximal effective dose of vitamin D is uncertain, but thought to be 400 to 1,000 IU/day. There is consensus that adequate vitamin D and calcium intakes are required for bone health. The therapeutic effects of most of the clinical trials of various drug therapies for osteoporosis have been achieved in the presence of calcium and vitamin D supplementation among control and intervention groups. Optimal treatment of osteoporosis with any drug therapy also requires calcium and vitamin D intake meeting recommended levels. The preferred source of calcium is dietary. Calcium supplements need to be absorbable and should have USP designation.
Physical activity is necessary for bone acquisition and maintenance through adulthood. Complete bed rest and microgravity have devastating effects on bone. Trials of exercise intervention show most of the effect during skeletal growth and in very inactive adults. Effects beyond those directly on bone, such as improved muscular strength and balance, may be very significant in fracture-risk reduction. Trials in older adults have successfully used various forms of exercise to reduce falls. High-impact exercise (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 been minimal.
Randomized placebo-controlled trials (RCTs) of cyclic etidronate, alendronate, and risedronate analyzed by a systematic review and meta-analysis have revealed that all of these bisphosphonates increase BMD at the spine and hip in a dose-dependent manner. They consistently reduce the risk of vertebral fractures by 30 to 50 percent. Alendronate and risedronate reduce the risk of subsequent non-vertebral fractures in women with osteoporosis and adults with glucocorticoid-induced osteoporosis. There is uncertainty about the effect of anti- resorptive therapy in reducing non-vertebral fracture in women without osteoporosis. In RCTs, the relative risk of discontinuing medication due to an adverse event with each of the three bisphosphonates was not statistically significant. The safety and efficacy of this therapy in children and young adults has not been evaluated. Since subjects in clinical trials may not always be representative of the community-based population, an individual approach to treatment is warranted.
Hormone replacement therapy (HRT) is an established approach for osteoporosis treatment and prevention. Many short-term studies and some longer term studies with BMD as the primary outcome have shown significant efficacy. Observational studies have indicated a significant hip fracture reduction in cohorts of women who maintain HRT therapy; still there is a paucity of trials with fractures as the endpoint. HRT trials have shown decreased risk of vertebral fractures, but there have been no trials of estrogen with hip fracture as the primary outcome.
The development of selective estrogen receptor modulators (SERMs) has been an important new thrust in osteoporosis research. The goal of these agents is to maximize the beneficial effect of estrogen on bone and to minimize or antagonize the deleterious effects on the breast and endometrium. Raloxifene, a SERM approved by the FDA for the treatment and prevention of osteoporosis, has been shown to reduce the risks of vertebral fracture by 36 percent in large clinical trials. Tamoxifen, used in the treatment and prevention of breast cancer, can maintain bone mass in postmenopausal women. However, effects on fracture are unclear.
There is a great deal of public interest in natural estrogens, particularly plant-derived phytoestrogens. These compounds have weak estrogen-like effects, and although some animal studies are promising, no effects on fracture reduction in humans have been shown. Salmon calcitonin has demonstrated positive effects on BMD at the lumbar spine, but this effect is less clear at the hip. Other than a recently completed randomized controlled trial of nasal calcitonin, no analysis of fracture risk is available. The PROOF study revealed a significant reduction in vertebral fracture risk at the 200 IU dose but not at the 100 IU or 400 IU dose. The absence of dose response, a 60 percent dropout rate, and the lack of strong supporting data from BMD and markers decrease confidence in the fracture risk data from this trial. Nonpharmacologic interventions directed at preventing falls and reducing their effect on fractures have been promising. These include studies to improve strength and balance in the elderly, as well as using hip protectors to absorb or deflect the impact of a fall.
Multifactorial approaches to preventing falls, as well as improving bone mass through combinations of interventions, suggest promising new directions.
- Should the Response to Treatment Be Monitored?
Several approaches have been introduced for the monitoring of patients receiving therapies for osteoporosis. The goals of monitoring are to increase adherence to treatment regimens and determine treatment responses. Many individuals do not continue prescribed therapy or do not adhere to a treatment protocol, even when enrolled in formal clinical trials. Monitoring by densitometry or measurements of bone markers have not been shown to be effective in improving compliance, and more research is needed about how to improve adherence to treatment protocols.
The best tests for monitoring treatment response would reflect the largest changes with the least error, and these assessment tools are not readily available. The Fracture Intervention Trial (FIT) reveals an additional problem with monitoring, the statistical phenomenon of regression to the mean. In this study, the larger the bone loss in the first year, the greater the gain the next year, for both the placebo and active treatment groups. Therefore, 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.
- Orthopaedic Management of Osteoporotic Fractures
While proximal femur (hip) fractures comprise nearly 20 percent of all osteoporotic fractures, this injury is among the most devastating of all the osteoporotic fractures and is responsible for the greatest expenditure of health care resources. The 1-year mortality rate following hip fracture is about 1 in 5. As many as two-thirds of hip fracture patients never regain their preoperative activity status. Early surgical management of hip fractures is associated with improved outcomes and decreased perioperative morbidity.
The adverse health, functional and quality of life effects of vertebral (spine) fractures are commonly underestimated, and such fractures are associated with increased mortality. The occurrence of a single vertebral fracture substantially increases the likelihood of future fractures and progressive kyphotic deformity. Due to the challenges of reconstruction of osteoporotic bone, open surgical management is reserved only for those rare cases that involve neurologic deficits or an unstable spine. Recently, there has been a burgeoning interest in two "minimally invasive" procedures for management of acute vertebral fractures, vertebroplasty and kyphoplasty, which involve the injection of polymethylmethacrylate bone cement into the fractured vertebra. Anecdotal reports with both techniques claim frequent acute pain relief; however, neither technique has been subjected to a controlled trial to demonstrate the benefits over traditional medical management. Furthermore, the long-term effect of one or more reinforced rigid vertebrae on the risk of fracture of adjacent vertebrae is unknown for both of these procedures.
Several issues are critically important to the orthopaedic management of acute osteoporotic fractures. It is most important to avoid the misconception that the only treatment required of an osteoporotic fracture is management of the acute fracture itself. Management during the perifracture period must consider blood clot prevention (mechanical or pharmacologic) in patients who will have delayed ambulation, the avoidance of substances that may inhibit fracture repair (nicotine, corticosteroids), and the frequent need for supplemental caloric intake. Finally, since less than 5 percent of patients with osteoporotic fractures are referred for medical evaluation and treatment, more aggressive diagnostic and therapeutic intervention of this population represents an opportunity to prevent subsequent fractures. Physicians treating the acute fracture should initiate an outpatient evaluation of the patient for osteoporosis and a treatment program, if indicated, or refer the patient for an osteoporosis assessment.
Source: National Institutes of Health
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