OSTEOPOROSIS

Definitions

In the USA, osteoporosis has been defined as a disease characterized by low bone mass and disruption of the bone tissue microarchitectural structure resulting in enhanced bone fragility, and a consequent increased fracture risk. [1]

The World Health Organization (WHO) has developed specific criteria for degrees of bone density and fracture risk based on bone densitometry studies. Under these definitions, the term Osteopenia is defined as a bone mineral density between 1 and 2.5 standard deviations below the young adult mean value. Osteoporosis is defined as a bone mineral density more than 2.5 standard deviations below the young adult mean normal. [2]

Contribution of genetic factors to osteoporosis :

The peak bone mass is achieved, on avarage, between the ages of 30 and 35 and the peak is largely determined by genetic factors. Undoubtedly some environmental factors, such as appropriate calcium intake and exercise, are necessary for full attainment of this programmed peak bone mass. [3] After about age 35, bone mass decreases over time and fracture risk increases. [4] In women, the degree of decrease in bone density is markedly exacerbated by the loss of estrogens after the menopause. Osteoporosis may also have a genetic basis. [5] The genetically determined length of the femoral neck also correlates directly with fracture risk, people with a longer femoral neck having an increased fracture risk. [6]

Since fracture risk is related to bone mass, these two genetic factors determine most of the ultimate fracture risk. [7] Daughters of women with osteoporosis have been noted to have reduced bone mass in the spine and probably also in the femoral neck; this puts them at increased fracture risk. The reduced bone mass in these daughters probably results from a low peak bone mass rather than from excessive bone loss. [8] In both women and men, interestingly, a low peak bone mass may be genetically associated with premature graying of the hair. [9] Recent advances have indicated that allelic variation in a single gene regulating the vitamin D receptor (VDR) may be responsible for as much as 75% of the genetic effect on bone density. [10]

The geometry of the hip joint is an independent risk factor for hip fracture. As mentioned above, there is an increased risk of fracture with longer femoral neck lengths. [11] Bone density and length of the femoral neck correlate with fracture risk, such that for each standard deviation decline in bone density there is a 2.7 fold increase in the fracture risk and each standard deviation increase in hip axis length is associated with a 1.8 fold increase in fracture risk. [12]

Environmental Contributions

Apart from genetic factors, physiologic and environmental considerations are also important in putting people at risk for osteoporosis. Bone is a living tissue. It serves as a storage site for calcium as well as structural material for the skeleton. Hormones regulate the ebb and flow of calcium in and out of bone.

Bone is constantly remodeled by the actions of two systems, the osteoclasts that remove bone and the osteoblasts that make new bone. [13] The osteoclasts are derived from macrophages and function to digest trenches within the bone in periodic cycles of activity. These trenches are then filled in with new bone produced by osteoblasts. When the amount of bone being removed by the osteoclasts exceeds the amount put back by the osteoblasts, the bone mass is reduced and eventually becomes increasingly subject to fracture. Sex steroids, estrogens in women and testosterone in men, act to limit osteoclast function to allow as much bone to be replaced as removed. When sex steroids are absent, such as in menopause or other hypogonadal states, osteoclast activity is greater than osteoblast activity and the result is a net loss of bone. In women going through natural menopause, this leads to a rapid decrease in bone mass during the 4-5 years after menopause with a slowed rate of bone loss thereafter. [14]

Vitamin D

Osteoporotic fracture in African-Americans tends to occur at later ages than in whites. [15] Vitamin D levels are commonly found to be diminished in white women and in both black women and men. Vitamin D supplementation has been advocated in the elderly population with low vitamin D levels. [16] It is of interest that South African black women have much higher bone mineral density than their African American counterparts. [17] This may suggest that dietary factors, such as low vitamin D and calcium content, related to an American diet, may be an important contributing factor to osteoporosis. In some studies, when vitamin D supplements and calcium were added to the diet of elderly nursing home residents, there was a decreased incidence of hip fracture. [18] Other studies using randomly selected patients did not show improvement with vitamin D alone. [19] This indicates that by selecting through genetic testing the population that would most benefit, one may be able to target specific therapy to groups of patients most likely to respond.

Sunny climes, such as Houston, generally provide sufficient Vitamin D through sun exposure, but shut-ins and nursing home residents may not have this benefit and may need dietary evaluation for supplemental Vitamin D needs. Vitamin D rich foods include fortified milk, fatty fish, egg and egg yolk (but watch cholesterol!). In at risk patients, recommended daily Vitamin D supplementation is about 200 to 400 IUs daily but no more than 800 without medical consultation.

Calcium & Exercise: Prevention and Therapy Issues

Calcium, along with exercise, is important to the attainment of the genetically determined peak bone mass in women that occurs between age 30 and 35. [20] In menopausal women who only exercised, bone loss continued while in women who exercised and took calcium supplementation, bone mass stabilized. [21] Women who exercised and took estrogen had a modest increase in bone mineral density. [22] Therefore, calcium and exercise are better than exercise alone, but not as good as estrogen replacement.

Very large amounts of exercise in women will cause hypothalamic dysfunction resulting in irregular cycles, low estrogen levels, and low bone mass with an increased risk of osteoporosis. [23] On the other hand, physical inactivity among the elderly is considered a major risk for hip fracture. [24] Exercise in the elderly can compensate for decreased muscle strength and may help prevent progression of osteoporosis, especially in the hip. [25] In addition, exercise in the elderly may modestly decrease the incidence of falls by improved muscle tone. [26]

There is evidence that women 200 years ago had stronger bones than their modern descendants of the same age. Skeletons of women buried in graveyards near London between 1729 and 1852 demonstrated much stronger bones, possibly indicating the value of hard work. [27] The present calcium recommendations are as follows:

Most modern diets are deficient in calcium and may contain only 400-600 mg of calcium daily. Foods that are particularly rich in calcium include milk and yogurt (about 300 mg per cup), Cottage cheese (about 90 mg per ½ cup), Sardines (about 350 mg for 3 oz), Broccoli (about 180 mg per cup), Turnip greens (about 100 mg per ½ cup), and fortified foods, especially orange juice.

Calcium supplements are often needed and are available over the counter. These supplements should generally be given with meals in divided doses. Calcium carbonate is inexpensive, easily available, and calcium dense (40% elemental calcium). It should be taken with meals to improve absorption with the acids produced by the stomach for digestion. Calcium citrate is better absorbed generally than calcium carbonate but is more expensive and contains only about 21% elemental calcium thereby requiring more tablets. Calcium phosphate is about 38% elemental calcium. Calcium lactate is only 13% elemental calcium and is generally not recommended as a supplement.

Sex Hormone Deficiency

In women, menopause occurs at about age 51 and is associated with a significant loss of bone mass unless hormone replacement therapy is started and continued. [28]

It is of interest that the final common pathway in maintaining bone mass in men is also via the estrogen receptor. In men, male hormones are converted in part to estrogen. Estrogen appears to be important in keeping osteoclast function suppressed, as was seen in an estrogen-resistant male with a genetic defect in the estrogen receptor in which the bone density was over three standard deviations below that of an age matched woman. [29]

Smoking

Smoking is a significant risk factor for osteoporosis. Men and women who were smokers had significantly reduced bone density in the hip in proportion to the amount smoked. [30] With the increasing number of women already at risk for osteoporosis engaging in smoking, the already high risk of osteoporosis will be increased significantly. The reason for this increased risk of osteoporosis may be that women who smoke have an earlier menopause by about 2 years, and therefore may increase the rate of bone loss earlier. [31] In addition, smokers weigh less than non-smokers which also increases the risk of osteoporosis. [32]

Weight

The only apparent advantage to obesity may be the lower risk of osteoporosis. Fat tissue converts weak androgens from the adrenal into estrogens that help maintain bone mass. [33] Another factor is that increased stress on the skeleton and more calcium intake may account for the higher bone mass. [34]

Medications

Long term use of high dose glucocorticoids [35] or thyroid hormone at supraphysiologic doses is associated with osteoporosis. [36] Fractures on high dose glucocorticoids may occur even at relatively greater bone mineral density values, indicating possible impairment in glucocorticoid treated individuals in normal bone support structures. [37]

Diet High in Acid Content

Since the bone also serves to buffer acids derived from the protein in the foods we eat, it has been proposed that diets high in food acids may result in loss of bone mineral. [38] Treatment with alkali in the form of oral use of bicarbonate preparations has been proposed as a treatment option if this cause of bone loss proves significant. [39]

Alcohol

People who use large amounts of alcohol may have lower bone mineral densities than those who do not. [40] Alcohol appears to poison the osteoblast, and thereby reduce the amount of bone refill that occurs with the bone remodeling cycle. [41] In addition, long term alcohol use is associated with nutritional disorders with reduced amounts of vitamin D and calcium. [42] There remains controversy however, as a recent epidemiological study found that alcohol was not a significant risk factor for osteoporosis. [43] Alcohol abuse often increases the risk of falls and thereby contributes to fracture, especially if osteoporosis is also present.

Summary

A 1995 major study by Cummings et al. followed 9516 white women over age 65 for over 4 years and concluded that a family history of hip fracture was the major risk factor for hip fracture in the patient group with a relative risk of 2.0 indicating the dominance of a genetic factor. [44] Other significant risk factors were previous fracture, being tall at age 25, hyperthyroidism, use of certain medications, high caffeine intake, lack of mobility, and visual impairment. [45] Weight gain since age 25 was associated with a lower risk of osteoporosis. [46]

Epidemiology

Up to 25 million Americans are affected by osteoporosis. One of every two women over the age of 50 and one of five men over age 50 will develop an osteoporotic fracture in their lifetime. Each year, there are 1.5 million osteoporotic fractures of the hip, spine and wrist. [47] In England, a country with socialized medicine, the statistics are equally dismal. One in four women will have a hip fracture by age 90 and one in eight men. One-quarter of all orthopedic beds in England are occupied by hip fracture patients with a 15% in-hospital mortality rate, a 33% one year death rate, and of those that live, only 66% return to their own home. [48]

The incidence of osteoporosis-related fracture has a female to male ratio of 4:1 at ages 55-64 and is nearly 1:1 for people older than 85 years of age, [49] giving added meaning to the ‘equality of the sexes.’

Medical Aspects

Silent

The first manifestation of osteoporosis is usually a fracture. Although genetic studies of the VDR gene may detect those with a higher risk of osteoporosis, the only way to detect the actual presence (phenotype) of osteoporosis is through bone densitometry studies. Since a variety of other disease conditions and environmental factors may also result in osteoporosis, bone densitometry would be expected to establish the diagnosis of osteoporosis in many more people than only those with the VDR osteoporosis-predisposed alleles.

Technological advances in equipment for use in detecting low bone mineral mass have exploded over the past decade. The present technology using dual x-ray bone densitometry devices provides rapid, safe, and precise measurements of bone density. [50] Examples of bone density studies are provided in the appendix.

Osteoporosis is one of the three common silent killers that have plagued modern civilization. The first, hypertension, almost always remains without symptoms until a stroke, heart attack or renal failure occurs. A simple blood pressure cuff measurement can detect the disease and lead to effective therapies that can prevent the adverse outcomes. The second, elevated LDL cholesterol, silently clogs arteries starting in young adulthood. This process may eventually choke off the vital supply of blood to organs throughout the body leading to heart disease, peripheral vascular disease, strokes, and renal failure. A simple blood test for the bad LDL cholesterol and the good HDL cholesterol can determine to a great extent who is at risk and who can benefit from preventive therapy. The third disorder in this series is osteoporosis. The superstructure of bone is quietly eaten away and over time the bone weakens and is subject to fracture.

Deadly and Disabling

Vertebral fractures cause loss of height, kyphosis, back pain, and significant changes in life style. [51]

Distal radius fractures affect younger people and are responsible for significant lost work days and short term disability. [52]

Hip fractures are associated with up to a 20% mortality over the several months following the fracture due to deep venous thrombosis, pneumonia, and pulmonary embolism. [53] About 60% of those that survive require help with activities of daily living. Up to 20% require long-term institutionalization in extended care facilities and only about 20% have complete return of function. [54] Many of those affected are themselves caregivers, caring for parents, spouses, children or grandchildren and after a hip fracture, are forced to give up this role and become recipients of care instead.

Preventable

The recent, exciting genetic studies of the VDR gene as a predictor of osteoporosis may give us pause to reconsider the patient groups most likely to benefit from interventions. It has long been reported that osteoporosis is mainly a disease of older white women. It is clear this myopic view will miss the large number of aging minority groups that develop osteoporotic fracture, as well as the significant number of men that develop osteoporotic fracture. It is also clear environmental factors remain a contributor to the development of osteoporosis in significant numbers of people.

Calcium replacement therapy, Vitamin D and exercise can help maintain bone mineral density in many patients. This is especially important in childhood and young adulthood in order to achieve the limit of peak bone mass dictated by genetics. (See previous section on Calcium and Exercise Issues).

In women, bone loss is most severe with estrogen deficiency. With the average age of natural menopause at about 51 years of age for women, significant bone loss becomes problematic within 4-5 years at the time of menopause. This bone loss can be prevented in large part by early recognition of the menopausal state, and life-long treatment with estrogen replacement therapy. This use of estrogen also reduces the risk of cardiovascular disease, the number one killer of men and women, by almost half. The benefits of estrogen replacement last for as long as estrogen is given. Bone loss will resume rapidly once estrogen therapy has been stopped. In postmenopausal women who still have a uterus, estrogen must be combined with a progestin to prevent the possible development of endometrial cancer. In women with a uterus on estrogen only, there is a 20% chance of developing endometrial hyperplasia at one year and a 60% chance after 3 years. Since different progestins have different physiological properties, the choice of a progestin may be significant in some patients. [55]

A minimum of 0.625 of Premarin appears to be needed to maintain bone density in post-menopausal women. In a minority of patients, this dose may not be enough to maintain bone mass. This can be discovered through follow-up bone density testing at between one to two years after therapy starts. A higher dose of estrogen may be needed in such patients to prevent further bone loss. Alternative preparations of estrogen include Estinyl at 0.02 mg or more daily, Estrace at 0.5 mg or more daily, the Estraderm patch at 0.05 mg or more daily, and Estropipate at 0.75 mg or more daily. Combinations of estrogen and progestin are also available in the form of PremPro or PremPhase. In women with a uterus, progestin combination therapy is needed to protect against endometrial cancer. Estrogen therapy should be continued for life since if therapy is discontinued, bone loss will recur.

Only about 1/3 of patients that qualify for estrogen replacement remain on therapy long-term. Therefore, almost 2/3 of all women who qualify for ERT will not be on therapy long-term and are at risk for osteoporosis.

In estrogen deficient women who cannot take estrogen because of a history of breast cancer or a fear of breast cancer, there are important alternatives. In women with breast cancer who have had a hysterectomy, tamoxifen can be used. Tamoxifen acts similarly to estrogen on bone and cholesterol but acts as an anti-estrogen on breast tissue. [56] As such, for patients with breast cancer, tamoxifen can help maintain bones and help prevent heart disease while helping prevent recurrence of the breast cancer. [57] Since tamoxifen can increase the risk of endometrial cancer in women with a uterus [58], there has been interest in a new drug in the same anti-estrogen class, raloxifene, which can maintain bone density [59] in an estrogen deficiency state and has beneficial effects on lipids, but does not appear stimulate the endometrial lining of the uterus. [60]

In men with hypogonadal disorders, replacement therapy with testosterone maintains bone mineral density for as long as testosterone is used. [61]

Calcitonin is an important option for many women with established osteoporosis. In women with bone pain from osteoporosis, calcitonin may act on the pain pathways and reduce pain. [62] Calcitonin prevents bone loss of trabecular bone in the spine and appears to have little effect on femoral cortical bone loss. A nasal preparation of calcitonin (Miacalcin Nasal Spray) recently became available at the end of 1995. Dosing at 200/IU daily of the nasal spray (one puff in alternate nostrils) is safe, convenient and cost-effective with monthly costs similar to alendronate (Fosamax) at between 40-50 dollars per month as of June 1996. [63] Miacalcin Nasal Spray is presently approved for use only in post-menopausal women five years or more past menopause.

A class of compounds called bisphosphonates can be given orally and enters into the bone where it inhibits the action of osteoclasts, resulting in less bone loss. The only bisphosphonate approved for use in the US as of 1996 is alendronate (Fosamax). [64] Alendronate is a suitable alternative to estrogen replacement therapy for those patients who cannot or will not use hormone replacement. Alendronate improves bone mass over a three year period (FDA study time so far is three years) and decreases fracture risk. It is important to take the medication properly. Alendronage can cause GI irritation and is poorly absorbed, and therefore proper instruction in use is CRITICAL. A 10 mg tablet is used each morning on an empty stomach with plain water only. No food or other beverage can be used for at least 30 minutes. Any other pills, mineral water, food or beverage taken with or within 30 minutes of alendronate will prevent any absorption of the drug from taking place! The pill should be taken in the upright position to prevent esophageal irritation.

There is only one treatment option that can actually significantly increase bone mass. Sodium fluoride will stimulate new bone formation, but the bone formed is unusually brittle and can result in cracks in the bone substance. [65] Fluoride treatment is considered experimental and is associated with significant side effects. It can be considered in severe osteoporosis where other options are not available. [66]

An additional simple method to prevent fracture is to prevent falls by hazard prevention, avoidance of sedatives or alcohol that can increase the risk of falling when rising from bed, and assistance with moving about. [67] A very simple preventive is the use of padding around the hips that can reduce fracture risk nearly to zero in studies done in nursing homes. [68] By identifying those patients particularly at risk through bone densitometry, these individuals can have these special precautions applied.

Costly Consequences

In addition to direct medical costs, many of those affected by osteoporotic fracture are caregivers for spouses, parents, children and grandchildren. After osteoporotic fracture, many of these caregivers become care-receivers and drain the economy of their much needed help. The annual direct and indirect costs of osteoporosis to the health care system have been estimated at $18 billion dollars in 1993 with $7 billion of that attributed to hip fracture. [69]

Applying national prevalence rates to Texas population figures for 1993, Texans experienced about 87,679 osteoporotic fractures with direct medical costs of $701,432,000, and lost opportunity costs of $315,644,400 for a total cost of about $1 billion in 1993. [70]

Direct medical costs alone are predicted to be as much as $45 billion in the next 10 years. [71] As the baby boom population ages, these direct and indirect costs are expected to exceed $60-$80 billion dollars by the year 2020. [72]

Issues of Medical Testing

Osteoporosis is late-onset, common and preventable. Stigmatization and discrimination have not been problems in spite of a large number of patients already tested and placed on preventive measures. Society has generally been supportive and understanding on the issue of osteoporosis, since many people have friends or relatives who suffer from the disorder. People are likely to believe they will suffer from the consequences of osteoporosis if they live long enough.

It is critical to have quality assurance in testing and interpretation. Bone densitometry is a proven technology that is accurate, precise, predictive of fracture and is presently used on large numbers of people world-wide. [73] Many endocrinologists, gynecologists, and internists are knowledgeable enough about treatment options to provide the patient with appropriate medical advice. The patient’s choice to have testing done at all should be vigorously defended, but appropriate medical information should be discussed with the patient so that an informed choice may be made.

Educational Programs

Most patients and physicians are not well informed on osteoporosis. A recent Gallup survey of women aged 45-75 demonstrated that only 18% identified hip fractures as being associated with osteoporosis, only 6% knew osteoporotic fractures could result in death, only 7% thought loss of height with age was due to osteoporotic spinal fractures, and 75% never discussed osteoporosis with their physician.

Conclusion

As the population ages, osteoporosis will become an epidemic in the next 20 years. Caregivers will become care-receivers as osteoporotic fractures take their toll. The economic and human costs will present a major challenge for the children of the present as they become members of the work force and are compelled to support their parents and grandparents. Society must be proactive, not reactive with a problem of this scope. Since therapy is effective if started before fracture occurs, high risk groups, such as menopausal women not on hormone replacement, should be informed of their bone density to allow them to decide with their physicians on therapy options. With the lack of power on the part of the consumer to determine what is covered in a health care policy, legislative action is required to ensure coverage for this major public health problem. I believe the elements supporting a mandate are present in this disorder, and it is the responsibility of the legislature to ensure society is protected from long-term harm and not sacrificed to short-term economic gain.

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12. Id

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