Fracture Prevention and Medical Treatment of Osteoporosis

FRACTURE PREVENTION AND
MEDICAL TREATMENT OF
OSTEOPOROSIS

Joseph M. Lane, Linda Russell, and Safdar N. Khan

Osteoporosis is a common human bone disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures.1 Based on World Health Organization criteria it is estimated that 15% of postmenopausal Caucasian women in the United States and 35% of women older than 65 years of age have frank osteoporosis.² As many as 50% of women have some degree of low bone density in the hip. One of every two Caucasian women will experience an osteoporotic fracture at some point in her lifetime. There is a significant risk, although lower, for men and non-Caucasian women to also sustain osteoporotic fractures. Patients with fragility fractures create a significant economic burden with more than 400,000 hospital admissions and 2.5 million physician visits per year.²

BASIC PATHOPHYSIOLOGY

The hallmark of osteoporosis is deficient bone density and connectivity.^3,4 The trabecular bone in an individual with osteoporosis will be thinner in dimension and have evidence of osteoclastic resorption, leading to disconnectivity of the trabecular elements. There is a deficiency of bone and a deterioration of the structural integrity of the underlying trabecular bone. Because trabecular bone has a much greater surface area, it is more readily affected by osteoporosis than the cortical bone.^5,6 The two major elements of cortical osteoporosis are tunneling resorption that can lead to stress fractures and the gradual thinning of the cortical bone. With aging, the body expands the cortical dimensions away from the epicenter of the bone. A 10% outward shift of bone can compensate for a 30% decrease in bone mass in terms of torque and bending, but it will not compensate for axial loading.

Males and females increase their bone mass with growth, achieving a peak bone mass by the age of 25. Thereafter, bone will be lost at a slow rate for men. Women have a precipitous drop around menopause, but after 60 years of age their rate of loss is identical to bone loss in men. In men and women there is a significant decrease in total bone mass as one approaches the age of 80, leading to a marked deficiency in mechanical properties. The summation of the strength of a given bone is related to the mass plus distribution, the relative ratio of trabecular to cortical component of the bone, and the structural integrity and connectivity of the trabecular and cortical elements.

Bone is a living tissue.⁶ It is constantly undergoing remodeling and repair. The process involves an identification of a molecular structural defect. Osteoclastic resorption then follows and resorption pits develop. This then is repaired with an ingrowth of osteoblasts replacing the bone. In individuals older than 40 years, the osteoblasts rarely bring the original bone surface back to the starting point, and, thus, every remodeling cycle leaves a small deficit of bone. The discrepancies in the rate of bone for resorption and formation lead to the gradual onset of osteoporosis (see below).

A bone has numerous functions.^3,6 Besides providing structural support for humans, it is the main mineral bank in which 98% of the body’s calcium is maintained, and it also is the site where blood elements are produced. The body has developed a complex program to maintain calcium levels within the body of which bone is the major mineral repository. Vitamin D is produced in the skin. For a Caucasian individual, 1 hour of sunlight is sufficient for the skin to produce 400 units of vitamin D. This form of vitamin D lasts for approximately 2 months. Inadequate exposure to sunlight, such as in those individuals who are housebound or in individuals with dark skin, will compromise this process. Vitamin D then is converted to 25-hydroxy vitamin D in the liver. The 25-hydroxy vitamin D has a 3-day half-life, and is still an inactive vitamin D metabolite. It can be degraded by P450 hydrolase enzymes of the liver, which often are stimulated by numerous drugs, including barbiturates. When the calcium level is low, parathyroid hormone is released, which stimulates the kidney to convert the inactive 25-hydroxy vitamin D to the active component, 1α, 25-dihydroxy vitamin D. The kidney retains calcium from the glomerular filtrate. The 1α, 25-hydroxy vitamin D sets off a process in the intestine that leads to calcium absorption from the gut. This active metabolite, working with parathyroid hormone, ultimately leads to the resorption of bone. The cessation of this process results in an elevation of serum calcium. Children are extremely capable of extracting calcium from their diet. However, as one gets older, the efficiency of intestinal calcium absorption decreases. In elderly individuals, calcium deficiency often will lead preferentially to resorption of bone rather than an increased absorption from the intestine.

Peak bone mass is achieved at the age of 25 years.7 Individuals who have a calcium deficiency during their adolescence will not achieve this peak bone mass. Bone mass accretion not only depends on the presence of adequate calcium in the diet but also on an adequate array of all essential nutritional components. Calcium requirements depend on the age of the individual. A dairy portion, which consists of milk, cheese, ice cream, or yogurt, contains approximately 250 to 280 mg of calcium per portion. The recommended daily intake of calcium is as follows: children require 700 mg or three dairy products; adolescents from the age of 10 to 25 years (when peak bone mass is achieved) require 1300 mg; adults require 800 mg; pregnant women require 1500 mg; lactating women require 2000 mg; postmenopausal women require 1500 mg; and patients recovering from a major fracture require 1500 mg. Girls who are 13 years of age often have inadequate calcium intake to achieve peak bone mass.^7,8 Numerous drugs including isoniazid, corticosteroids, heparin, tetracycline, furosemide, and caffeine can decrease calcium retention. Drugs that are detoxified in the liver with the P450 hydrolase system, particularly barbiturates, are suspected of decreasing calcium retention.

Hormonal status is critical in achieving and maintaining peak bone mass.⁶ Women who are premenopausal lose approximately 0.3% of their skeleton per year unless they are taking adequate levels of calcium. At menopause, or for every year that women are amenorrheic or oligomenorrheic, they will lose 1 to 3% of their skeleton. Women who are postmenopausal by surgical hysterectomy and oophorectomy, or who are naturally post-menopausal, will have equal amounts of bone loss when matched for length of time after cessation of normal cycles. Thus, rapid bone loss occurs when women stop having normal menstrual cycles.

Bone is extremely sensitive to exercise and mechanical load.⁴ Under a no-load situation bone will be lost. Low loads will maintain bone. High loads will remodel bone to withstand the new loads. Very high loads will lead to bone failure. Exercise, including impact and programs such as walking and dancing, when coupled with calcium intake has been shown to maintain or increase the appendicular skeleton in elderly individuals.⁹ Exercise is inadequate to protect the spinal trabecular bone in the woman who is perimenopausal, although it can clearly decrease the rate of loss as compared with the individual that does not exercise. Overexercise leading to amenorrhea is another issue.^10,11 In one study of runners, Drinkwater et al¹⁰ reported that women who had amenorrhea had a bone mass of 1.12 g per cm², whereas eumenorrheic women who ran half the distance but maintained normal menstrual cycles had a bone mass of 1.30 g per cm² and statistically had more bone. In fact, women who did not exercise but maintained normal nutrition and menstrual cycles had a higher bone mass (1.20 g per cm²) than the women with amenorrhea who exercised. This showed that exercise to the point of developing amenorrhea is a deleterious state. Male long-distance runners also have low bone mass with an approximate decrease of 10 to 20% and an increased bone turnover. It is not clear whether the hormonal state is the cause or just a comarker. Warren and Stiehl¹² think that just reestablishing menstrual cycles without adequate calories is ineffective.

DEFINITION AND DIAGNOSIS

Low bone mass is the most accurate predictor for increased fracture risk.^1,13 An individual who has a bone mass that is one standard deviation below his or her peers will have a 1.9-fold increased risk of spinal fracture and 2.4-fold increased risk of hip fracture. These data are based on a slowly changing skeletal state. Acute changes in bone status, such as produced by steroids, can profoundly weaken bone before the bone mass reflects that finding. Bone mass is determined by numerous methods. The technique that has been used in most bone centers for the treatment of patients is based on dual energy X-ray absorptiometry (DEXA). In this situation the amount of mineralized tissue within an aerial section of the spine or hip is analyzed and expressed as grams per cm². Comparisons can be made with their peers and with a young, healthy adult population with peak bone mass. If the individual is more than 1.5 standard deviations below his or her age-corrected peer group (derived from cross-sectional studies in the United States), that individual probably has a secondary cause of osteoporosis that needs additional evaluation. The bone mass in the individual then should be compared with the peak bone mass in young adults, which characterizes whether the individual has osteoporosis according to criteria from the World Health Organization.2 If the individual is within one standard deviation, she or he is considered healthy. If she or he is between one and 2.4 standard deviations below peak bone mass, she or he is considered to have significant bone loss and osteopenia. If she or he is 2.5 standard deviations below peak bone mass, the patient is considered to have frank osteoporosis, and if the patient has a fragility fracture, she or he is considered to have severe osteoporosis.

There are alternate methods to determine bone mass besides the DEXA.^8,13,14 These methods include a single energy X-ray absorptiometry and peripheral dual energy absorptiometry, which measures bone density in the forearm, finger, and sometimes the heel. A second method is radiographic absorptiometry. This is based on a standard radiograph, or computer-generated radiograph of the hand with a metal wedge in the same field. The quantitative computed tomography (CT) scan measures the trabecular bone at several sites, but most commonly is used to evaluate the spine. It uses 20 times the radiation and has a poorer precision compared with the DEXA. The ultrasound densitometry accesses the heel, patella, tibia, and peripheral sites, and measures several properties of bone. All the peripheral results are at a distance from the hip and the spine and only have a 0.75 correlation, at best, with those central readings. Second, their ability to recognize change with treatment is much more limited. These methods are excellent in identifying people who have osteopenia and are at risk for bone loss. However, in terms of treatment and follow-up of individuals the consensus at this time is to use DEXA.

Bone density determination^14,15 is indicated for women who are perimenopausal and women who are postmenopausal to determine their need for hormonal replacement therapy and other antiosteoporotic therapies, for individuals with known metabolic bone disorders who are taking agents that affect bone mass, for individuals with low energy fractures, and for individuals with a high number of risk factors for having osteoporosis develop. It also is indicated to monitor efficacy of treatment.

The bone mass determination shows the investigator the current skeletal mass, but does not provide information as to the metabolic activity.¹¹ Several markers have been developed for bone formation and bone resorption. Bone formation markers are bone-specific alkaline phosphatase and osteocalcin. Markers for bone resorption are based on collagen breakdown products released into the urine. The most common products measured are the N- and Ctelopeptides of the collagen cross-link area and the pyridinoline and the deoxypyridinoline cross-links. They are extremely sensitive to determining bone turnover rates. DEXA will provide the current bone mass state, and the resorption perimeters will indicate the rate of bone loss.

RISK FACTORS

Osteoporosis is associated with numerous risk factors, some that can be modified and some that cannot be modified.^1,8 Major factors that cannot be modified are: personal history of a fracture as an adult or a history of a fracture in a first-degree relative. Minor factors include Caucasian race, advanced age, female gender, dementia, and poor health or frailty. The potentially major risk factors that can be modified are associated with current cigarette smoking and low body weight (<127 pounds). The minor factors that can be modified are estrogen deficiency, low calcium intake, alcoholism, impaired eyesight, recurrent falls, inadequate physical activity, and poor health and frailty depending on the cause. Health and frailty are related to risk factors that can be modified and risk factors that cannot be modified.

There is clear evidence of genetic predisposition to osteoporosis.^1,6,8 Individuals who have blond hair, red hair, fair skin, freckles, easy bruisability, hypermobility, a small build, and adolescent scoliosis commonly are reported as having a genetic predisposition to develop osteoporosis.⁶ The major risk factors are independent of bone mass and their presence raises the level of concern for any given level of bone mass. Low body weight and recent loss of bone, a history of fracture (personal or in a first-degree relative), and smoking all should raise the concern for osteoporotic fractures.⁸