骨头健康: Osteoporosis 预防战略
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Osteoporosis is an important health problem affecting mature women. It is a skeletal disorder characterized by loss of bone mass, deterioration of microarchitecture, and a decline in bone quality, all of which lead to an increased vulnerability to fracture. Many aspects of gynecology and obstetrics can affect bone health. Americans with osteoporosis or with low bone mass, approximately 80% are women. Osteoporosis-related fractures will occur in more than 40% of women over the age of 50. Hip fractures will occur in more than 40% of women over the age of 50. An estimated 1.3 to 1.5 million fractures occurring annually are attributed to osteoporosis, accounts for about 15% of the total. Within 1 year after a hip fracture, up to 20% of the victims will die, 25% of the survivors will be confined to long-term care facilities, and 50% will experience long-term loss of mobility. Spinal fractures can be associated with pain, loss of height, and deformities. Osteoporosis also is associated with tooth loss and the resorption of alveolar ridge. It is a potentially devastating and debilitating disease, and it is a public health threat in the United States. The fractures it causes have significant physical consequences, including limited mobility, deformity, and chronic pain, as well as functional limitations, such as a loss of independence. Fractures and osteoporosis also have serious psychosocial outcomes that can include anxiety, depression, loss of self-esteem, and the lack of rewarding social roles.
The purpose of this document is to review the diagnosis, evaluation, and treatment of osteoporosis. Obstetricians and gynecologists play a major role in the prevention, diagnosis, and treatment of osteoporosis as outlined in this document. It is intended as an educational tool that presents current information. It is clear that age is one of most important factors related to bone quality, but exactly how age affects bone quality is not entirely clear. Changes in bone mass and microarchitecture have been well characterized. The other components that comprise bone quality are not well understood. Compliance (the consistency and accuracy with which a medication is initially followed) and persistency (the length of time a regimen is continued) are the most challenging aspects of osteoporosis management, both for patients who must take the medication and for physicians who treat this disorder. Because medication adherence remains an important issue in osteoporosis, education and attention to patient preferences for medications may help prevent the fractures that lead to the negative outcomes of osteoporosis.
The World Health Organization (WHO) defines low bone density, or osteopenia as a bone mineral density between 1 and 2.5 standard deviations below the young adult mean and the osteoporosis be defined as a bone mineral density 2.5 standard deviations or more below the young adult peak mean. At the spine and hip, a 1 standard deviation decrease in bone mass is associated with approximately a two-fold increase in fracture risk (1). T score is the number of standard deviations above or below the mean average bone density value for young adult women. WHO provided criteria for diagnosing osteoporosis by dual-energy X-ray absorptiometry (DXA) scan, and this is the only test that has been validated for osteoporosis diagnosis. The most widely recommended method of diagnosing osteoporosis in the United States is bone densitometry. DXA of the lumbar spine and hip is the preferred method. Although peripheral sites such as the wrist and heel are predictive of osteoporosis and fractures, they are not suitable for monitoring treatment effects.
Key Bone Density Definitions
Osteoporosis A disease of the bone that is characterized by a predisposition to low-trauma fractures caused by low bone mass and disordered bone architecture. Defined by the WHO as a bone density T-score at or below -2.5 of normal peak bone density values for sex-matched young adults. A diagnosis of osteoporosis can also be made by proving the presence of a low-impact vertebral, hip, or wrist fracture.
Low bone mass (previously osteopenia): Defined as a bone density T-score between -1 and -2.5 below the young adult mean.
T-score: The difference in standard deviations between the value for the patient being tested and the mean value of a sex-matched group of adults aged 25 to 45 years. A T score of 0 indicates that the person being tested has a BMD that is at the mean for adults aged 25 to 45 years. Four standard deviations approximate the range of measurements from the 5th to 95th percentile.
Z-score: The difference in standard deviations between the mean BMD of the patient being tested and a group of people of the same age and sex. A low Z-score may warrant an investigation for a secondary cause of osteoporosis, such as hypercalcemia, low 25-hydroxy vitamin D, or malabsorption syndrome.
The main determinants of peak bone mass and bone quality are thought to be genetic (2). Many gene polymorphisms that affect bone quality have been identified. Other genetically linked findings such as changes in the Wnt signaling pathway, lipoprotein receptor-related protein 5 pathway, non-enzymatic glycation of collagen, and homocysteine levels also appear to contribute to the complexity of bone quality (2). Widely different age-adjusted hip fracture rates for women have been reported from around the world from 1 in 100,000 person-years among Nigerian black women to 421 in 100,000 person-years among Norwegian white women (3). Within the United States, there also is considerable variation in hip fracture rates, most notably between racial and ethnic groups. Caucasian women have the highest rates of hip fractures, and Mexican American women have rates in between the other two groups (4). These racial and ethnic differences are important in counseling and management because fracture rates do not always correlate with bone mineral density (BMD) across ethnic groups. For example, Chinese American women typically have lower areal BMD than Caucasian American women, but lower rates of hip and forearm fracture (4). It is postulated that greater cortical density and thicker trabeculae compensate for less trabeculae in smaller bones. Thus, both BMD and micro-architecture appear to play distinct roles in fracture vulnerability. However, apart from Chinese Americans, fracture rates correlated with BMD data collected in the National Health and Nutrition Examination Survey (NHANES) 2005-2006, which reported in African American women, and the lowest BMD in Caucasian American women (5).
The functional part of bone is the remodeling unit. Bone can be divided into two major types: cortical and trabecular. Cortical bone forms the outer shell of all bones and accounts for 75% of total bone mass. Trabecular bone is the spongy, interlacing network of struts that forms the internal support within the cortical bone. Trabecular bone is concentrated in the vertebral bodies and pelvis and at the ends of the long bones. It accounts for 25% of total bone mass, but counts for most of the surface area of the bone. Bone remodeling units are limited to the bone surface. Because trabecular bone has large surface area, it has a higher turnover rate than cortical bone (6).
The remodeling cycle can be conveniently divided into four phases: resting, resorption, reversal and formation. Each remodeling cycle may take several months to complete. During resting phase, stem-cells from the bone marrow are attracted to the bone surface and differentiate into osteoclasts. During the resorption phase, the osteoclasts remove bone using an acid pH to dissolve the minerals and proteolytic enzymes to digest the bone proteins. During reversal phase, the osteoclasts cease removing the bone and mesenchymal stem cells are attracted to the bone surface and differentiate into osteoblasts. During the formation phase, osteoblasts make new bone by first laying down a protein matrix (osteoid), which is then mineralized. Bone formation and resorption is an ongoing process that usually is balanced in young adults who have adequate nutrition and exercise and normal puberty.
Bone mass peaks at approximately 30 years in both men and women. After reaching peak bone mass, about 0.4% of bone is lost per year in both sexes. In addition to this loss, women also lose approximately 2% of cortical and 5% of trabecular bone per year for the first 5 to 8 years following menopause (7). With aging, the coordinated balance between osteoclasts and osteoblasts may be disturbed, resulting in excessive bone loss. In women who are recently menopausal, excess bone loss is commonly due to excessive osteoblasts resorption. In later postmenopausal years, suppressed osteoblasts activity and inadequate formation of bone may play a major role in the progression of osteoporosis.
Factors Affecting Bone Mass
Bone mass is affected by these factors: family history, hormone levels, lifestyle and habits, nutrition, medications, and diseases that affect bone metabolism. Many studies have shown that the risk of osteoporosis is greater for white and Asian women than for African American women. Mexican American women have an intermediate risk. These racial differences are probably due, in part, to genetic determinants of body size, body composition, and bone metabolism. Genetic factors play a role in determining bone mass.
Estradiol, testosterone, progesterone, cortisol, parathyroid hormone, thyroxine, growth hormone, and insulin all can influence bone mass. The mechanism by which estradiol regulates bone mass are not completely defined. Many lifestyle factors and habits influence bone mass. Cigarette smoking, excessive use of alcohol and high caffeine intake may be associated with decreased bone mass and an increased risk of hip fracture. Dietary calcium intake is an important modular of bone mass, especially during childhood, adolescence, and advanced age. Childhood calcium intake appears to influence adult hipbone mass (8).
Vitamin D and its metabolites are essential to calcium metabolism and maintenance of mineral balance. In the United States, vitamin D deficiency rarely occurs except in select populations, such as those who are institutionalized with inadequate dietary intake and insufficient exposure to the sun. High protein diets acutely increase calcium excretion, but long-term, high protein diets are not associated with excess bone loss. Diets high in phosphorus can result in excess calcium loss, but daily phosphorus intake less than 2,00 mg is not harmful to bone (recommended daily allowance in menopausal women is 700 mg).
Systemic medications such as glucocorticoids, thyroxine, and heparin can cause decreased bone mass. They have a direct effect on bone, causing inhibition of bone formation and enhancing bone resorption, and also decrease calcium absorption from the intestine and increase renal excretion of calcium. Hyperthyroidism is associated with decreased bone mass. Many metabolic bone diseases are associated with bone loss. These diseases often can be differentiated based on the measurement of serum calcium, phosphorus, and alkaline phosphatase. Osteoporosis can be caused by systemic diseases of the endocrine, hematopoietic, gastrointestinal and connective tissue systems. When osteoporosis is caused by systemic diseases, it is called secondary osteoporosis.
Physical activity, adequate nutrition, and good health also are necessary for bone health (9). Exercise during the growth phase of life has the added advantage of modulating bone geometry in a way that enhances bone strength beyond what an increase in BMD alone can provide and may have longer lasting benefit. The most effective type of exercise to recommend has not yet been determined. However, a Cochorane analysis concludes that weight-bearing, resistance exercises and aerobics have a beneficial effect on spine BMD (no fracture data) and walking is beneficial for hip BMD (9).
Risk Factors for Osteoporotic Fractures
Diagnosis needs to take into account other risk factors, including age, sex, white race, smoking and a family history of osteoporosis. There is no current accurate measurement of overall bone strength. Imaging technology is now available to determine bone mass with minimal radiation exposure, high accuracy, and high precision. DXA is preferred by most authorities. The precision of the measurement is approximately 1%. The radiation dose is less than 5 mrem. All modern DXA devices have an examination time in the range of 5 minutes. DXA instruments are available, which measure bone mass at peripheral sites such as in the forearm. Measurement of forearm, wrist, or hand bone density may not predict hip fractures as accurately as the direct measurement of hip-bone mass. One disadvantage of DXA is that bone spurs, aortic calcium, and arthritis may falsely elevate the reported bone density. Ultrasound bone mass measurement is a new technique that offers the potential advantage of avoiding exposure to ionizing radiation.
Bone mass tests typically report three values:
In addition to bone density instruments, bone mass can be estimated through serial height measurements. Measurement of current height and comparison to reported maximal adult height can help establish the presumptive diagnosis of osteoporosis. Osteoporosis is likely to be present if the patient has lost more than 1 inch in height from her maximal adult height and the clinical setting is consistent with a diagnosis of osteoporosis. Biochemical markers can be useful to help identify women with high bone turnover and to monitor the effects of osteoporosis treatment. Markers that measure the rate of bone formation include serum bone alkaline phosphatase, serum osteocalcin, and serum procollagen I extension peptides. Markers that show the rate of bone resorption include urinary N-telopeptide, collagen crosslinks, urinary deoxypyridinoline, and urinary hydroxyproline (5).
Other bone densitometry technologies can be used for predicting fracture risk, but the WHO classification does not apply to these systems. Peripheral DXA can be used at the heel, finger, or wrist. Quantitative ultrasound densitometry has no radiation exposure because the technology involves the use of either broadband ultrasound attenuation or speed of sound to derive a quantitative measurement of the bone. Common sites for measurement are the heel, patella, and tibia. Peripheral sites cannot be used to monitor treatment. Quantitative computed tomography can measure volumetric BMD of trabecular and cortical bone, either centrally at the spine and hip or peripherally at the forearm or tibia. There are substantially greater amounts of radiation exposure with this modality. Vertebral fracture assessment involves lateral spine imaging that can be performed by the lumbar spine DXA densitometer. A medical history of vertebral fracture is a reason to treat an at-risk woman even in the absence of a T-score of less than -2.5. A clinical diagnosis of osteoporosis can be established in the absence of imaging if there is a medical history of a low-trauma fracture in an at-risk woman (11). Low-trauma fractures are fractures that occur in a situation that would not be expected to cause fractures in most individuals (e.g. a vertebral fracture from opening a window or a simple fall from a standing position). These examples are in contradiction to a fracture caused by falling off a ladder or a fracture resulting from a car accident where higher trauma is present.
Summary of Clinical Laboratory Data in Common Metabolic Diseases of the Bone
Bone Turnover Markers
Bone turnover markers are byproducts of bone resorption (deoxypyridinoline, N-telopeptides, and C-telopeptides from the breakdown of type I collagen) and bone formation (osteocalcin, bone-specific alkaline phosphatase, and procollagen type I N-terminal propeptide associated with bone matrix synthesis). They can be measured in urine or serum to determine a high bone turnover state of high bone turnover, which may indicate higher risk of fracture. High levels reflect a state of high bone turnover, which may indicate higher risk of fracture. Bone turnover markers have been used in clinical trials of osteoporosis therapies to demonstrate group response to treatment. Changes in bone turnover markers occur earlier than changes in BMD and can be used to ascertain the effect of treatment more promptly. Use of bone turnover markers in the management of individuals is more challenging because levels vary from day to day and throughout a single day. Bone turnover markers cannot be used to diagnose osteoporosis, and the usefulness of markers as an incentive for adherence has been questioned (12).
A healthy life-style is important for those at risk for osteoporosis. Cessation of smoking eliminates the effects of nicotine on estrogen binding. Moderation in alcohol and caffeine intake will improve general health, and weight-bearing exercises provide mechanical stimulation for bone remodeling. Sedentary life-style is associated with reduced bone mass. The benefits of physical exercise include maintenance of bone mass and an increase in muscle strength and coordination. The risk of falling increases substantially with aging. Most falls that result in hip fractures occur indoors. The living environment should be monitored to reduce the risk of falling. Prevention of osteoporosis begins in childhood and adequate calcium intake is important. Many children and adolescents do not achieve the recommended daily intake of calcium. Insufficient calcium intake also can accelerate age-associated bone loss.
The two types of exercise necessary for bone health are weight-bearing and muscle-strengthening exercises. Weight-bearing exercises help build bone and keep bones strong. Strength training or resistance training helps to improve strength, balance, and flexibility. Perhaps its most important contribution is in preventing falls. Unfortunately, drawing evidence from research in this area is difficult for a variety of reasons. Until further research is conducted, knowledge about the impact of exercise on multiple aspects of osteoporosis is still insufficient.
Institute of Medicine Recommended Dietary Allowance for Calcium and Vitamin D
Before initiating treatment, it is important to consider the possibility of secondary causes of osteoporosis. Fractures in a relatively young postmenopausal woman or a BMD lower than expected of age (e.g. a Z-score below normal for her age group) suggests the need to check for secondary causes of osteoporosis. An initial approach to evaluating for secondary causes of osteoporosis is suggested by American College of Obstetricians and Gynecologists (ACOG) are (13):
Treatments have been broadly classified as antiresorptive or anabolic, depending on the primary mechanism of action. There are many options for treating osteoporosis.
This class of drugs reduces bone resorption by inhibiting osteoclasts; slows bone loss and increases bone mass. Bisphosphonate are analogues of inorganic pyrophosphate, and a number of these are currently under development. Vertebral fractures are reduced by 48% in the women treated with alendronate and risedronate (14),(15). They are poorly absorbed from gastrointestinal tract and are recommended to be taken in the morning with 8 ounces of water, prior to any food or beverage. No food or beverage should be taken for the next 30 minutes to allow the alendronate to be absorbed. After taking alendronate or risedronate the woman should remain in an upright position, either sitting or standing to minimize the possibility of abdominal discomfort. The major side effects are abdominal discomfort, upper gastrointestinal bleeding, and musculoskeletal pain. One potential advantage of alendronate and risedronate are that they remain tightly bound to the surface of the bone for many years. It is not recommended for the patients with the renal failure or upper gastrointestinal problems. US Food and Drug Administration (FDA) has approved their use for the prevention of osteoporosis.
The four bisphosphonates approved in the United States, alendronate, risedronate, ibandronate, and zoledronate, have been extensively studied in large randomized controlled trial that have demonstrated anti-fracture benefit. All bisphosphonates significantly reduce vertebral fractures by 32-65% (14),(15). Risedronate reduces non-vertebral fractures, and both alendronate and zoledronate significantly reduce hip fracture specifically. These drugs are classified as antiresorptive agents because the mechanism of action is inhibition of osteoclast resorption of bone. Inhibition of osteoclasts leads to a lesser decrease in bone formation by osteoblasts, but the net result is an increase in BMD and a decrease in bone turnover. Duration of effect after discontinuation may vary. Discontinuation of alendronate after 5 years of treatment resulted in maintenance of bone turnover markers below baseline for 5 years with BMD remained stable or decreased slowly (16). Discontinuing risedronate after 2 years of treatment resulted in significant loss of BMD during the first year (17).
Zoledronate is contraindicated in patients with acute renal failure or creatinine clearance of less than or equal to 35 mL/min. Patients should be screened for renal disease before zoledronate infusion because renal failure has occurred after infusion in patients with compromised renal function. Caution with regard to renal function should be exercised with other drugs in this class as noted in the product information sheets. Hypocalcemia should be corrected before the use of these drugs.
Government Approved Bisphosphonates for Postmenopausal Osteoporosis
Adverse effects of bisphosphonates include musculoskeletal aches and pains, gastrointestinal irritation, and esophageal ulceration. Potential risks reported after marketing include osteonecrosis of the jaw, seizures, atypical fractures of the femoral shaft, and esophageal cancer. A precise understanding of the true risk of these events has been difficult to determine because of the lack of data on the incidence of these problems in the general population. Although rare cases of osteonecrosis of the jaw have been reported in patients using bisphosphonates for osteoporosis (18). It has been seen most commonly after dental extractions in those being treated with large intravenous doses of bisphosphonates in association with supportive cancer therapy (19). There is no requirement to discontinue bisphosphonates for dental procedures. However, there is likely to be no harm in discontinuing a bisphosphonate temporarily for a dental procedure, if the patient so desires, given the long duration of action of bisphosphonates
Denosumab (Prolia), an antiresorptive treatment, is a human monoclonal antibody to the receptor activator of nuclear factor-kB ligand. The receptor activator of nuclear factor-kB ligand binds to the receptor activator of nuclear factor-kB on the surface of osteoclasts and promotes proliferation and differentiation of these osteoclasts. The antibody blocks this interaction therein decreasing bone resorption and increasing BMD as a result (20). Denosumab was approved in 2010 for treatment of postmenopausal women with osteoporosis who are at high risk of fracture. Studies revealed a vertebral and hip fracture reduction of 68% and 40%, respectively (20). Denosumab (Prolia) is administered subcutaneously every 6 months. A higher rate of infections that required hospitalization was seen in the initial trials. However, concerns about suppression of the immune system leading to increased rates of cancer were not substantiated.
Partial Estrogen Agonists and Antagonists
Raloxifene (Evista) was the first drug in the class of partial estrogen agonists and antagonists (also known as selective estrogen receptor modulators) approved for the prevention and treatment of osteoporosis. It works as weak estrogen agonists in some systems, and estrogen antagonists in others. Raloxifene decreases the number and activity of osteoclasts and is approved for the prevention and treatment of postmenopausal osteoporosis. It decreases the incidence of vertebral fractures by 30% to 50% and increases BMD in the spine and femoral neck (21). Raloxifene is associated with a reduced risk of estrogen-dependent breast cancer, and may lower the risk of heart disease and stroke in women at high risk. However, the long-term effects of raloxifene on the vascular system are unknown, and increased risk of thromboembolic events similar to that reported with estrogens has been observed. As a result of its tendency to cause or exacerbate hot flashes, raloxifene is not recommended for newly menopausal women or for the treatment of vasomotor symptoms. However, it can reduce the risk of breast cancer in postmenopausal women at low risk of the disease, and is currently being evaluated for use in reducing the incidence of breast cancer in women at increased risk.
Calcitonin (Miacalcin, Fortical) is a synthetic polypeptide based on salmon calcitonin, is available in a subcutaneous injectable form and as nasal spray. It inhibits bone resorption and is approved for the treatment of osteoporosis in women who are postmenopausal for at least 5 years. It increases vertebral bone mass and significantly reduces new vertebral fractures. It has been shown to reduce vertebral fractures and to reduce bone pain associated with vertebral fractures (22). Objection to injectable now can be avoided by intranasal spray. Risks are: development of neutralizing antibodies-effect and absorption is variable. One spray in one nostril delivers the recommended dose of 200 IU of salmon calcitonin. Fracture reduction is less robust than with other agents and was not seen in early postmenopausal women. It should not be used until women are 5 years from menopause. Adverse effects include flushing and nausea with subcutaneous injection and local irritation with nasal spray.
Estrogen / Hormone Therapy (multiple brands)
It was one of first treatments for osteoporosis. It was widely used and showed effectiveness by increasing bone density at the spine and hip and by reducing hip, vertebral, and non-vertebral fractures. Estrogen / hormone therapy was also used to manage menopausal symptoms, and was widely used prior to the release of Women's Health Initiative (WHI) study findings in 2002. This trial found that estrogen / hormone therapy was effective at reducing hip fractures and preventing colon cancer, but that unexpectedly, women taking estrogen or estrogen plus progestin were found to have statistically significantly higher rates of cardiovascular disease, stroke, dementia, breast cancer, and other conditions that were studied. The investigators concluded that health risks associated with estrogen / hormone therapy outweighed the benefits (23). As a result of these findings, estrogen's status was changed by the FDA. It is currently approved for the prevention of osteoporosis in women who are also experiencing menopausal symptoms. In cases where women do not have such symptoms, they should use another agent for the prevention of osteoporosis.
Contraindications are: undiagnosed abnormal genital bleeding; known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease; known or suspected estrogen-dependent neoplasia; active deep vein thrombosis, pulmonary embolism, or a history of these conditions; active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction); liver dysfunction or disease; known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency); known hypersensitivity to any of the ingredients in these products; and known or suspected pregnancy.
Anabolic Agents for Osteoporosis