CHAPTER 15

OSTEOPOROSIS

Barrie Raik, M.D.

  Table of Contents

                Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture. The clinical manifestations of osteoporosis relate almost exclusively to its associated fractures. Many diagnostic and therapeutic options have become available over the last 10 years. Osteoporosis should no longer be thought of as an inevitable consequence of aging, but as a condition to be prevented or treated.

Burden of Suffering

                There are 1.3 million osteoporosis-related fractures each year in the United States: 250,000 hip, 500,000 spine and 240,000 wrist.[i] Osteoporotic fractures are associated with minimal to moderate trauma (usually a fall from standing height or less). They increase in frequency with age and have a higher incidence in women than men. A 50 year-old white woman has a 40 percent risk of any fracture by age 70. The lifetime risk of a hip fracture is 15 percent in white women, eight percent in black women and about six percent in white men. Hips fractures frequently lead to loss of independence, and are associated with a 15 to 20 percent reduction in expected survival in the first year.[ii] Fifty percent of women who sustain a hip fracture never return to their previous lifestyle. Vertebral fractures lead to chronic pain and “dowager’s hump.” Wrist fractures frequently result in disability, as do fractures of the ankle, knee, pelvis and proximal humerus. Osteoporosis leads to over 13 billion dollars in total yearly costs in the U.S.[iii] The incidence of fractures and their associated cost will increase because of the increasing number of elderly people.

Pathophysiology

            Peak bone mass is achieved in early adulthood and depends mainly on genetic heritage, adequate diet and physical activity. Bone remodeling occurs in an orderly fashion, with bone resorption (osteoclast activity) followed by bone formation (osteoblasts); a process called coupling. When the bone resorption and formation are not matched, there is remodeling imbalance. Less bone is replaced than was removed and there is less bone mass and higher fracture risk. The structure of the bone is weakened by loss of trabecular plates and the bones are fragile and more likely to fracture with low impact trauma.

Risk Factors

                Bone mass or bone mineral density (BMD) is the major predictor of increased risk of fracture. The balance of osteoclastic bone resorption and osteoblastic bone formation favors formation until the mid-thirties, when bone density reaches its peak. Both men and women lose bone at a rate of 0.3 to 0.5 percent per year beginning in the fourth decade, but at menopause women experience accelerated bone loss at a rate up to 3 to 5 percent a year for 5 to 7 years.[iv] Subsequently, the rate is one-half to one percent per year.

                In both men and women, the age-associated decrease in bone density leads to an increase in fracture risk. Every five years, the incidence of hip fracture doubles, from 4/1000 at age 70 to 74, to 9/1000 (75 to 79), to 17/1000 (80 to 84). Similarly, the risk of fractures doubles for each standard deviation below the mean of bone density measurement (see below). The risk factors listed in Table 1 have been identified in the Study of Osteoporotic Fractures.[v]

TABLE 1: Risk Factors for Osteoporotic Fracture

                Additional risk factors are history of hyperthyroidism, treatment with anticonvulsants and higher caffeine intake. Women with low bone density and more than five risk factors have an especially high risk of hip fracture and should be the focus of preventive efforts.

                Secondary causes of osteoporosis include multiple myeloma, lymphoma, leukemia, steroid use, Cushing's syndrome, Addison's disease, hyperparathyroidism, anorexia, malabsorption and chronic liver disease. While men and African American women have higher peak bone mass and less osteoporosis, osteoporotic fractures do occur in these individuals, especially with advanced age and other risk factors.

Prevention

                Maximizing peak bone mass and minimizing loss during and after menopause would prevent much osteoporosis. A diet with adequate calcium intake, particularly in childhood and adolescence, and regular weight-bearing exercise are basic to all osteoporosis prevention programs. Other general measures include vitamin D intake, tobacco cessation, good general nutrition and, in the elderly, attention to fall-prevention strategies. This includes good lighting, sturdy shoes, clear pathways in the home, appropriate walking aids, physical therapy and, in frail nursing home patients, hip padding.  In a 1998 review of the evidence for primary prevention of postmenopausal osteoporosis,[vi] calcium and vitamin D reduced the incidence of nonvertebral fractures in healthy elderly individuals. 

Screening

                There are several existing tests that can be used to assess asymptomatic patients at risk for osteoporosis, including dual energy x-ray absorptiometry (DEXA) and quantitative computerized tomography (QCT). Plain x-rays reveal osteopenia only when some thirty percent of bone mass has been lost. DEXA is precise, accurate, relatively fast and involves minimal radiation exposure; it is the favored diagnostic test and is discussed below. The test is expensive, however, and there are no data to support routine screening for osteoporosis in early menopause. If a diagnosis of osteoporosis would change a patient’s management (by helping to determine if hormone replacement therapy is appropriate, for example) screening DEXA studies may be reasonable. 

            The controversy over who to test is addressed in the 1998 report "Osteoporosis: review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis."¹ The decision to test should be made in the context of the particular treatment being contemplated. Taking into consideration a woman's age and other risk factors (of the four major risk factors: thinness, smoking, prior fracture and family history) we can determine whether the knowledge of bone density will affect treatment plans. If a 60 year-old woman has one or more risk factors, knowing the bone mineral density (BMD) will be helpful. If a woman has no risk factors, wait until age 65 to measure BMD. This recommendation by the National Osteoporosis Foundation, supported by evidence, may be incorporated into the next USPSTF guidelines.

Diagnosis

                The World Health Organization has defined osteoporosis and osteopenia using bone density measurements. On most DEXA scans, the patient is scanned at three sites: the radius, femoral head and lumbar spine. The results are reported in bone mineral density (in gm/cm2) in comparison with age and sex-matched controls (Z-score) and in comparison with controls at peak bone mass, or “young adult mean” (T-score). Normal bone mass is defined as a T-score within one standard deviation (SD) of young adult mean. Osteopenia is defined as a T-score one to 2.5 SD below the young adult mean, and osteoporosis is defined as a T-score greater than 2.5 SD below the young adult mean. A Z-score value greater than two SD below age-matched controls suggests a secondary cause of osteoporosis. Osteoporosis may also be diagnosed when a low trauma fracture occurs in an older patient. Both T-scores and Z-scores can be used in making decisions about testing and treatment. Bone mineral density is generally accepted as a surrogate marker for fracture risk; an excellent discussion of the strengths and weaknesses of this stance can be found in one of the Users’ Guides to the Medical Literature.[vii]

            Tests of bone turnover include biochemical markers of bone formation: serum alkaline phosphatase and osteocalcin, as well as markers of bone resorption: urinary excretion of collagen cross-linked C-telopeptide, hydroxyproline and deoxypyridinoline.[viii] They may prove to be important in selection of therapy, but at present their role in patient management is unknown. Monitoring response to treatment is another area of uncertainty, with some recommending serial BMD measurements and others advising against such a strategy.^1,7

Treatment

                Clinical data, such as previous fractures, fall risk and age, are important features in determining if and how a patient should be treated for osteoporosis.[ix] Primary prevention of fracture with calcium is inexpensive and safe, and should be considered for the general population. Avoidance of tobacco use and alcohol abuse, regular weight bearing exercise and other fall prevention strategies are also appropriate for all patients. Decisions regarding HRT will usually depend on other factors in addition to BMD, including additional risk factors, presence or absence of a personal or family history of breast or endometrial cancer, and use and tolerance of previous therapies.  

Calcium supplementation has been shown to benefit elderly women with osteoporosis by slowing the rate of decrease in bone density and reducing the incidence of symptomatic fractures.[x]^,[xi] During menopause, the effect of estrogen withdrawal causes so much bone loss that extra calcium cannot compensate. The National Institutes of Health recommend 1000mg of daily calcium for premenopausal women and 1000 to 1500 mg for postmenopausal women. The National Academy of Sciences similarly recommends 1200mg/day for post-menopausal women.[xii]^,[xiii] Men have similar needs for calcium. Food sources (milk, yogurt, cheese and calcium supplemented orange juice) are preferable, but difficult for most people to achieve.

Calcium supplements vary in the amount of elemental calcium and in the efficacy of absorption. Calcium carbonate is 40 percent calcium while calcium citrate is 24 percent calcium but easier to absorb. Calcium carbonate must be taken with meals. Calcium carbonate (Os-cal) 650 mg twice a day added to an average diet will provide adequate calcium for most people. Over-the-counter Tums EX calcium provides 300 mg of calcium and can be easier to tolerate for some patients; four to five tabs a day are recommended. The main side effect of calcium supplementation is occasional constipation. 

            Vitamin D is necessary for calcium absorption. Most middle-aged Americans have adequate levels of vitamin D, but many elderly do not. Vitamin D levels can be measured, but it is safe to empirically treat women with 400 to 800 IU of vitamin D a day. Calcitriol (1,25 vitamin D) should be reserved for those who specifically require it, as it can cause hypercalcemia if overused.

            Hormone replacement therapy (HRT) during menopause decreases fracture risk by preventing bone loss due to estrogen deficiency and by increasing bone density at the spine and hip. Estrogen binds to bone receptors and reduces bone resorption. Epidemiologic studies have shown that more than five years of HRT reduces the risk of hip fracture by 50 to 60 percent.[xiv] There are few randomized trials of hormone replacement therapy affecting fracture risk.[xv]^,[xvi] When estrogen replacement is discontinued, however, the bone loss resumes at its previous rate. Decisions regarding hormone replacement therapy are complex and are discussed at length in Chapter 12.

            Bisphosphonates reduce bone loss by adsorbing to bone and inhibiting osteoclast-mediated bone resorption. Alendronate (Fosamax) was approved in 1995 for the treatment of osteoporosis, and in 1997 for its prevention (at a dose of 5mg in normal early postmenopausal women with T score > 1 SD below norm). A recent study showed an increase in bone density at both hip and spine over three years and a 50 percent reduction in vertebral fracture rate (from 6.2 percent to 3.2 percent), [xvii] results comparable to those seen with HRT. The effects of alendronate and estrogen on bone density are additive.[xviii] The results of the Fracture Intervention Trial of over 4000 women show a 36 percent reduction in the rate of hip fractures in women with the lowest bone density.[xix] Alendronate may also reduce the back pain and disability associated with existing vertebral fractures.[xx] Long term efficacy and safety of alendronate are unknown; its main adverse effects are gastrointestinal, with erosive esophagitis and gastritis of greatest concern. The 10-mg pill must be taken with water on an empty stomach and the patient may not eat or lie down for 30 minutes after taking it. Alendronate is an alternative therapy for postmenopausal women with osteoporosis in whom hormone replacement therapy is contraindicated, refused or poorly tolerated. The optimal duration of therapy is unknown at present. Because bisphosphonates remain in bone, it is possible that the effects will last years after the drug is stopped.

            Calcitonin interferes with osteoclasts and inhibits bone resorption. Nasal spray formulations are approved for the treatment of osteoporosis, in addition to older parenteral formulations. Studies have shown an increase in bone density at the spine as well as a reduction of vertebral fractures, but no changes at the hip;[xxi] similarly, there has not been a demonstrated decrease in the incidence of hip fractures.[xxii] Calcitonin is recommended for use in women more than 5 years post menopause who have had a vertebral fracture or are at high risk of developing one. The dose of nasal spray calcitonin (Miacalcin) is 200 IU daily. Nasal dryness and irritation are the most common side effects. Calcitonin has an analgesic effect that makes it especially useful for women with vertebral fractures and chronic back pain.

            Raloxifene is a selective estrogen receptor modulator (SERM) that was approved for use in prevention of osteoporosis in 1998. It has mixed estrogen-agonist and estrogen-antagonist activity. In a two-year study in postmenopausal women, raloxifene therapy caused a decrease in bone resorption and an increase in BMD at spine and hip.[xxiii] It also decreases LDL cholesterol, and does not stimulate endometrial growth. A more detailed discussion of raloxifene can be found in Chapter 12.

            Fluoride stimulates bone formation. Early studies showed an increase in bone density but also found an increased risk of fracture. A 1995 trial of lower dose, slow release fluoride showed a 65 percent decrease in the incidence of vertebral fractures and no increase in nonspinal fractures.[xxiv] A 1998 study showed a small reduction in vertebral fractures when low dose fluoride and calcium were given over 4 years.[xxv] The slow release formulation is not commercially available and is not approved by FDA; we do not recommend fluoride therapy at this time.

            Exercise is associated with increased bone mass in young women, although this may be due to associated habits (calcium intake, estrogen replacement or exercise in earlier years). Exercise that produces strain on bone is necessary to strengthen bone. Thus running is better than swimming. Walking is a weight bearing exercise and has been shown to improve bone density. Prescribing exercise is also appropriate, because increased muscle strength, coordination and flexibility may reduce the risk of fracture.

            Future treatments under investigation include additional bisphosphonates (risedronate, and others), recombinant parathyroid hormone, and insulin-like growth factor.

            Summary

            Osteoporosis is a major public health problem, especially in elderly women. Hormone replacement therapy and calcium supplementation reduce the risk of developing osteoporosis and can be empirically prescribed to high risk women. Secondary prevention for patients who have already had one fracture is also effective. There are no data showing better outcomes in people who are screened for osteoporosis with bone densitometry, but a recent review of the evidence lead the National Osteoporosis Foundation  to recommend bone densitometry to women over 65 whose decisions about treatment would be affected.¹ 

Acknowledgment

We thank Dr. Ethel Siris for her helpful comments and suggestions.