Osteoporosis

Abstract

Osteoporosis is a disorder of decreased bone mass, microarchitectural deterioration, and fragility fractures. Osteoporosis is widespread and can affect people of all ethnic backgrounds and many older women and men. An essential element in preventing osteoporosis is the achievement of normal peak bone mass. Adequate nutrition, appropriate calcium and vitamin D intake, regular menstrual cycles and a well balanced exercise program of exercise are essential elements in achieving peak bone mass. At menopause women undergo accelerated bone loss. Thereafter, women and men gradually lose bone mass. A loss of one standard deviation give rise to an enhanced twofold risk of spine fractures or a 2.5 risk of hip fracture. Bone mass is determined by dual energy xray absorptiometry, quantitative computed tomography scan, and a peripheral ultrasound. Dual energy xray absorptiometry has outstanding precision (within 1% to 2%), and has the ability to show the efficacy of drug intervention. Peripheral measurements may identify osteoporosis but only have a 70% correlation with hip and spine bone mass. Dual energy xray absorptiometry determines bone mass in a patient but the bone collagen breakdown products (N-telopeptide crosslinks) establish the current rate of bone loss.

Major risk factors leading to fragility fracture include low body weight, history of fracture, family history of osteoporosis, and smoking. All individuals should ingest adequate calcium and vitamin D, exercise, and prevent falls. Women with low bone mass, high urinary bone collagen breakdown products, and/or major risk factors should consider hormone replacement therapy or a selective estrogen receptor modulator (Evista), calcitonin and bisphosphonates (alendronate). These agents successfully increase bone mass and limit fracture risk. Men at risk for fragility fractures respond similarly as women to alendronate and calcitonin. Although vertebral compression fractures can occur spontaneously, hip fractures are attributable to low bone mass coupled with a fall. Hence, fall prevention programs in addition to medical treatment are critical in the prevention of fragility fractures.

Osteoporosis is a common human bone disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures.³³ 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.⁵⁵ 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 their lifetime. There is a significant risk, although lower, for men and nonCaucasian 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.⁵⁵

Basic Pathophysiology

The hallmark of osteoporosis is deficient bone density and connectivity.^19,34 The trabecular bone in an individual with osteoporosis will be thinner in dimensions 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.^26,27 The two major elements of cortical osteoporosis are tunneling resorption that can lead to stress fractures, and the gradual thinning of the cortical thickness. 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 will 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 occurring around menopause, but after 60 years of age their rate of bone 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.²⁷ It constantly is 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.^19,27 Besides providing structural support for humans, it is the main mineral bank in which 98% of the calcium is maintained, and also is the site for which 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 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 house bound 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 out of their diet. However, as one gets older, the efficiency of the intestinal system decreases. In elderly individuals, calcium deficiency often will lead preferably to resorption of bone rather than an increased absorption from the intestine.

Peak bone mass is achieved at the age of 25 years.³⁶ Individuals who have 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.^36,37 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 barbituates, are suspect of decreasing calcium retention.

Hormonal status is critical in achieving and maintaining peak bone mass.²⁷ Women who are premenopausal lose approximately 0.3% of their skeleton per year. Unless they are taking normal physiologic levels of calcium, there is no bone loss. At menopause, or for every year that women are amenorrheic or oligomenorrheic, they will lose 2% of their skeleton. Women who are postmenopausal by surgical hysterectomy and oophorectomy or who are postmenopausal naturally will have equal amounts of bone loss when matched by years. Thus, rapid bone loss occurs when women stop having normal menstrual cycles.

Bone is extremely sensitive to exercise and mechanical load.³⁴ Under a no load situation, bone will be lost. Low loads will maintain bone. High loads will remodel bone to with-stand the new loads. Very high loads will lead to bone failure. Exercises, including impact and programs such as walking and dancing, when coupled with calcium have been shown to maintain or increase the appendicular skeleton in elderly individuals.⁵⁰ Exercise is inadequate to protect the spinal trabecular bone in the woman who is perimenopausal although it clearly can decrease the rate of loss as compared with the individual that does not exercise. Overexercise leading to amenorrhea is another issue.^11,12 In a study of runners, Drinkwater et al¹¹ reported that women who had amenorrhea had a bone mass of 1.12 g/cm², whereas eumenorrheic women who ran half the distance, but maintained normal menstrual cycles, had a bone mass of 1.30 g/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/cm²) then 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 Stiehl⁵² 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.^33,47 An individual who has a bone mass that is one standard deviation below his or her peers will have a 1.9 increased risk of spinal fracture and 2.4 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 xray absorptiometry (DEXA). In this situation the amount of mineralized tissue within an aerial section of the spine or hip bone 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.⁵⁵ 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 DEXA.^18,37,47 These methods include a single energy xray absorptiometry and peripheral dual energy absorptiometry, which measure 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 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 who are at risk for bone loss. However, in terms of treatment and followup of individuals the consensus at this time is to use DEXA.

Bone density determination^18,43 is indicated for women who are perimenopausal and women who are postmenopausal to determine their need for hormonal replacement therapy and other other antiosteoporotic therapies, individuals with known metabolic bone disorders who are taking agents that affect bone mass, individuals with low energy fractures, and 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.¹² 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 C-telopeptides of the collagen crosslink area and the pyridinoline and the deoxypyridinoline crosslinks. They are extremely sensitive to determining bone turnover rates. Dual energy xray absorptiometry 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.^33,37 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 lb). 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.^27,33,37 Individuals who have blond hair, red hair, fair skin, freckles, the ability to bruise, hypermobility, a small build, and adolescent scoliosis commonly are reported as having a genetic predisposition to have osteoporosis develop.²⁷ The major risk factors are independent of bone mass and their presence raises the level of concern for any given level of bone mass. The low body weight and recent loss of bone, a history of fracture in the individual or in a first-degree relative, and smoking all should raise the concern for osteoporotic fractures.³⁷

Diagnosis

More than 65% of individuals presenting with a compression fracture will be asymptomatic.^19,27 Most individuals will lose as many as 2 inches in height because of narrowing of the discs. Any height loss greater than 2 inches should raise suspicions of a compression fracture. The etiology for fractures could be trauma, localized lesion, or underlying metabolic bone disease. The predominant forms of underlying disease other than osteoporosis are bone marrow abnormality, endocrinopathy, and osteomalacia. A low hemoglobin level, elevated sedimentation rate, and abnormal immunoelectrophoresis should identify multiple myeloma. Approximately 1% of patients with osteoporosis will present with this disorder. Other than an early menopause, the major endocrinopathies are Cushing's disease, Type I diabetes, hyperparathyroidism, and hyperthyroidism. Primary Cushing's disease is rare. Iatrogenic Cushing's disease is widespread because of steroid use for numerous medical disorders and can be determined easily by history. Osteoporosis associated with Type I diabetes is worse in individuals under poor insulin control with subsequent glucosuria. Hyperparathyroidism is best identified by an intact parathyroid hormone assay, and elevated N-telopeptide collagen breakdown products. Most patients are diagnosed with hyperparathyroidism before the kidney stones and brown tumors develop. Hyperthyroidism often is associated with overmedication and is a common presenting state for women of large girth with osteoporosis. One study indicated that these individuals frequently have hypothyroidism and take enhanced doses of thyroid medication in part to control their weight.²⁷ Individuals who are at risk can best be identified with a suppressed thyroid stimulating hormone assay. Osteomalacia is present particularly in individuals who live in the urban northern United States. At New York Presbyterian Hospital, 8% of individuals with hip fractures have frank osteomalacia, and more than 40% have some degree of malnutrition.⁴¹ The common laboratory abnormalities of individuals with osteomalacia are low calcium, low phosphate, low 25 hydroxy vitamin D, high alkaline phosphatase, and a high level of parathyroid hormone. Alkaline phosphatase will rise when an individual sustains a fracture, but it takes 5 days to do such. Therefore, a patient presenting with a fragility fracture and an initial high alkaline phosphatase level probably has an underlying high turnover state disease until proven otherwise. Once the secondary causes of osteoporosis have been worked out, the clinician then must decide whether the osteoporosis is high or low turnover (see below).

Consequences of Hip Fractures

Hip fractures are the most debilitating problem in individuals with osteoporosis. Two-thirds of the money received for the treatment of osteoporosis is spent toward the treatment of patients with hip fractures.³³ Sixteen percent of women will have a hip fracture in their lifetimes.³⁷ Hip fractures lead to a 15% increase in mortality within the first year and more than 70% of survivors have a profound diminution of function. Men have less than 50% the risk of women for hip fracture but twice the mortality rate.

The load to fracture correlates well with the femoral bone density.^20,23 Therefore, decreased bone density increases the risk of weakening the bone. An older individual's femur has 1/2 the strength and 1/3 the energy of absorption as compared with a femur in a younger individual. Given a direct blow to the trochanter, a young individual still has 20% more bone strength than the injury will impart. However, an elderly individual has passed the mechanical capability by 50%. The reason that there are less fractures than falls is that most individuals do not directly injure their trochanter. One study has shown that more than 90% of fractures do occur from falls and that the majority of falls occur in the home between the hours of noon and 6:00 PM.¹ Falls, in fact, are the primary risk factor for hip fracture. A fall to the side would increase the risk of a hip fracture by 5.7-fold in a patient who is ambulatory, and 21.7-fold in a patient in a nursing home. One decrease of one standard deviation of bone density will increase the femoral neck fracture risk approximately 2.7-fold. The lower the body mass index, the higher the risk of a hip fracture, particularly in the nursing home population. Thus, a fracture is related to the initial starting bone mass, the trauma to that bone, the ability to repair a microfracture before it becomes a macrofracture, the quality of the bone, the general health of the individual, and the age of the individual.

Classifications of Osteoporosis

Riggs and Melton⁴⁵ have defined two forms of osteoporosis. Type 1 osteoporosis occurs in women over men 6:1. It is related to estrogen deficiency associated with vertebral fractures and usually is unrelated to calcium intake. Type 2 occurs in older individuals, approximately 75 years of age, and it is now 2:1 women over men. Trabecular and cortical bone hip fractures are the main problem in patients with Type 2 osteoporosis and the fractures are related to a lifetime of inadequate calcium intake. It was presumed by Riggs and Melton⁴⁵ that Type 1 osteoporosis was high turnover and Type 2 was low turnover, although it now is recognized that high and low turnover osteoporosis can occur in both age groups. In high turnover osteoporosis there is an increased number and depth of osteoclastic resorption sites and the normal osteoblast effort, when repairing the site, cannot totally fill the defect. In low turnover osteoporosis there are normal or decreased osteoclastic resorption sites; however, the osteoblasts are markedly inactive. This could be brought on by genetic etiology, senility, or drugs such as methotrexate. An excellent method to differentiate these types of osteoporosis is through the collagen breakdown products.^16,27,43,46 In the N-telopeptide assay, the normal is from 5 to 65 nmol of bone collagen equivalents per millimole of creatinine. However, in the healthy, younger individual, most N-telopeptide crosslink values are in the area below 35. Values greater than 35 indicate a higher resorption rate. Those values in the order of 50 or higher are twice those of the young individual and provide evidence of a relative increase in this resorption rate.

Therapy

There are numerous agents that have been developed to treat osteoporosis. The antiresorptive agents are estrogens, and selective estrogen receptor modulators, calcitonin, and bisphosphonates. Bone stimulators all are experimental and have not been approved by the Food and Drug Administration. These include the fluorides, parathyroid hormone, and parathyroid hormone related peptide analogs. The general recommendation for all patients with osteoporosis is to ingest a physiologic level of calcium and vitamin D, perform an appropriate exercise program, and adopt fall prevention.

Calcium and vitamin D will decrease bone resorption and will mineralize the osteoid. Several studies have shown that patients taking calcium and vitamin D have a higher bone mass and a lower fracture rate.^4,9 Particularly in the nursing home populations, calcium and vitamin D have been associated with a decrease in the hip fracture rate by 25%, and less mortality. Calcium and vitamin D, however, will not prevent spinal bone loss in woman who are perimenopausal. Conversely, the appendicular skeleton will be maintained in all age groups in woman who are premenopausal and elderly women who obtain physiologic levels of calcium and vitamin D coupled with adequate exercise. There are various forms of calcium preparations; the most commonly used preparations are calcium carbonate and calcium citrate.²³ Calcium carbonate requires gastric acidity to be dissolved. Numerous medications including H-blockers may interfere with this function. Calcium citrate, however, is digested easily by patients of all ages and patients with all gastric conditions. In terms of kidney stone production, calcium carbonate will increase the risk of kidney stones. However, calcium citrate actually is protective.³⁰ It therefore is recommended that calcium citrate be used in elderly individuals, in individuals with dyspepsia, in men with a higher history of having kidney stones, and in patients with constipation. Magnesium is usually readily available in the normal diet; however, in individuals who are alcohol abusers or who are malnourished, magnesium may be beneficial. Moreover, magnesium leads to amelioration of constipation, and, therefore, 400 to 500 mg of magnesium during the day may prevent constipation in individuals who take calcium.

Estrogen has been the most studied and used agent for prevention of osteoporosis.^{13,14,21,27,28,30,31,35,37} Estrogen will decrease bone resorption. Estrogen in the dose equivalent of 0.625 mg of Premarin (Wyeth-Ayerst Laboratories, Philadelphia, PA) will increase bone mass approximately 2% per year.³¹ Once an individual stops taking estrogen, the individual will lose 2% of bone mass per year, and 7 years after terminating estrogen, bone mass will return to baseline levels unless the individual begins to take another antiresorptive agent. Estrogen has been shown at this dose to decrease fractures at all sites by approximately 50%.³¹ A recent study indicated that a lower dose (0.3 mg) was unable to show any efficacy in terms of hip fracture prevention within 3 years.²⁴ Estrogen has numerous nonosseus effects, including a favorable modification of the cardiolipid profile, which has been translated into decreased risk for heart disease and longer survival. It also protects teeth from migration. Estrogen also improves the genitourinary physiology leading to less urinary tract infections and better vaginal function. There is some suggestion that it may ameliorate, to some degree, the effects of Alzheimer's disease and improve cognitive functioning.^40,56

Estrogen is associated with an increased risk of thrombophlebitis. It causes as much as a 10-fold increase in uterine cancer if unprotected.²⁶ The co-use of progesterones can totally eliminate this increased risk. Estrogen has been associated with approximately a 2.5% per year increased rate of breast cancer over the baseline, which translates after 10 years to a 30% increased risk. Thus, rather than 10 to 11 women per 100 getting breast cancer, estrogen will increase the rate to 14 to 15 per 100.^13,21 Because the majority of patients older than 70 years who have breast cancer are not dependent on estrogen, it has been thought that the relative added risk may decrease in the elderly patient when estrogen's nonosseous benefits are best felt. Thus, estrogen therapy should be offered to the patient twice, once at menopause when bone loss will be greatest, and second when the patient reaches age 70 when secondary benefits are desirous. There are various forms of estrogen. Most are beneficial, and equivalent doses to 0.65 mg of Premarin are effective in approximately 80% of patients. After a woman has been taking estrogen for 3 to 6 months, the N-telopeptide should have declined by 30%. If it has not, the question should be raised as to the dosage of estrogen. Patients who smoke and individuals who are very thin may require a higher estrogen dose. There often is breast engorgement in women, and, therefore, a slow build up of estrogen may be important to allow the individual to tolerate the estrogens. A continuous combination of estrogen with 2.5 mg of progestins not only is very effective in terms of bone protection but also prevents menstrual cycles. There is breakthrough bleeding within 5 years of menopause; however, when a woman starts taking estrogen beyond that point, the breakthrough bleeding is very rare. Women taking estrogen require yearly followup by their gynecologist and yearly mammograms. The combination of estrogen with other antiresorptive agents may be synergistic (see below).

A series of estrogenlike agents have been developed. Originally, tamoxifen was used as an antiestrogen, particularly for patients with breast cancer. However, bone cells were shown to be responsive to tamoxifen.⁴² It has been shown that individuals taking tamoxifen have 70% of the benefit of estrogen in terms of maintaining bone mass.⁶ Tamoxifen has not been used as an osteoporotic agent because 70% of women have significant postmenopausal symptoms and a high incidence of uterine cancer. However, this observation contributed to the development of the selective estrogen receptor modulators.^10,17,22 These are a series of agents that often can compete for the estrogen binding site and seem to function more like an estrogen at bone. The bone cells consider these agents to be estrogens. They work effectively as antiresorptive agents. They can change some of the lipid profile, particularly the triglycerides, but there is very little change in the high density lipid fraction with these agents. There is no uterine hypertrophy and the risk of uterine cancer appears to be no more than normal. There are early data to suggest there is a decreased risk (possibly 73%) of breast cancer in patients using raloxifene over patients who do not use raloxifene.⁷ A current trial now is underway comparing selective estrogen receptor modulators with tamoxifen as to their preventive action against breast cancer. In terms of osteoporosis, raloxifene, which is the first release selective estrogen receptor modulator, can decrease the risk of vertebral fracture by approximately 40% to 50%. There is no reported protection in terms of the hip. There is an increase in bone mass which approximates approximately 2/3 the improvement related to estrogen.¹⁵

Raloxifene (Eli Lilly, Indianapolis, IN) is associated with an 8% incidence of leg cramps and an increased risk of thrombophlebitis that is comparable with estrogen. Because raloxifene also enhances postmenopausal symptoms, it is not recommended in the first 5 years of menopause. The use of raloxifene for protection against breast cancer now is being considered.⁸

Calcitonin is a non-sex, nonsteroid hormone that may play a role in the skeletal development of the embryo and fetus. It has been used effectively in patients with hypercalcemia and in patients with Paget's disease.^{27,28,38,39,44,52} One study has shown that subcutaneous injections of calcitonin, approximately 100 units per day, have been effective in treating patients with osteoporosis.²⁵ A nasal form of calcitonin recently has been introduced⁴⁹ and at the dose of 200 units per day, seems to increase bone mass in the spine, comparable with estrogen, and decreases spinal fractures by 37%.⁵ There is no benefit in terms of hip fractures as of 5 years. Lower doses of calcitonin and higher doses of calcitonin may not be as effective in protecting against fractures. Whether this is a peculiarity of the study is not clear. Calcitonin does have the other benefit of providing some analgesia. It has been used in patients with painful osteoporotic fractures and will not interfere with fracture healing. Two percent of patients complain of dry nares.

Bisphosphonates are pyrophosphate analogs in which the linking central oxygen is replaced by a long carbon chain with either hydroxyl groups or a nitrogen group.^{20-23,26-28,51,53} The bisphosphonates are nondegradable analogs. They function by binding to the osteoclast-resorbing surface and act as a non-degradable shield. If absorbed by the osteoclast they have a secondary mode of inhibiting the osteoclast function. Short chain bisphosphonates such as in chlondronate, lead to interference with the Krebs cycle. The long chain nitrogen containing bisphosphonates such as alendronate interfere with the prenylation of the lipid membrane. Bisphosphonates have a very low bioavailability and less then 1% is absorbed when taken orally. The first bisphosphonate approved by the Food and Drug Administration for the treatment of osteoporosis is alendronate (Merck, West Point, PA). This has been shown to increase bone mass in the hip and spine, comparable with estrogen. It decreases the risk of all fractures by approximately 50% after 1 year of treatment.^3,7,29 Regardless of the degree of which the bone mass is enhanced, there is an equal protection for all patients against fractures. Those individuals with the lowest bone mass gain and those in the quartile of the highest bone mass gain had equal protection against fractures by alendronate suggesting an improvement in bone quality. Alendronate has been associated with esophageal irritation and as many as 30% of individuals have had esophagitis. However, in a carefully controlled study, the rate seems to be comparable with the patients in the placebo group.²⁹ The slow build up of alendronate, such as one pill taken the first week and then two pills taken the second week until the patient is taking 10 mg daily, has lead to more than 98% compliance from patients who were treated at the authors' institution. The low dose of alendronate, such as 5 mg per day or 10 mg three times per week, is used as a preventive dose. The higher dose is used successfully for the treatment of patients with osteoporosis. Alendronate, in animal studies, seems to inhibit osteolysis around prostheses.⁴⁸

Pamidronate has not been approved for treating patients with osteoporosis, but has been used for treating patients with metastatic disease, hypercalcemic malignancy, and Paget's disease. At the authors' institution, intravenous doses of pamidronate have been successful in treating osteoporosis in this population group.

The first generation bisphosphonate, etidronate, when used in doses of 400 mg daily for 2 weeks followed by 11 weeks of calcium and multivitamin has been reported to decrease fractures and increase bone mass when used repeatedly.^51,53 Patients who take etidronate do not have the gastric side effects associated with alendronate. However, the data were best reported for the first 2 years and long-term use may produce a mineralization defect. There has been a question about its use, and the Food and Drug Administration never has approved etidronate for use in patients with osteoporosis in the United States, but it is used in patients in Canada.

A series of new bisphosphonates has been released for treating patients with Paget's disease and are being developed as osteoporotic agents, including intravenous agents that require very short administration time and numerous new oral agents. Although they have not been approved by the Food and Drug Administration for treating patients with osteoporosis, they will be used for those patients within the next year.

Combination agents have been tried. Ninety-percent of individuals who did not respond to estrogen therapy have shown a benefit when they began taking alendronate. Twenty percent of individuals who did not respond to alendronate therapy have shown improvement when they began taking estrogen. A recent study³² indicated that a combination of alendronate and estrogen are superior to the single agents in terms of bone density augmentation. There were no data in terms of fracture healing protection.

To date, the Food and Drug Administration has approved estrogen, alendronate, and calcitonin for the treatment of patients with osteoporosis, and has approved low dose alendronate and raloxifene for the prevention of osteoporosis. None of these have been labeled specifically for men; however, the bisphosphonates and calcitonin have been effective in men. Premenopausal individuals have to be evaluated and treated very carefully in terms of drug choices, including calcium and vitamin D. If menstrual cycles are becoming slightly irregular, some physicians have prescribed birth control pills or a postmenopausal dose of estrogen and progesterone, giving the patient at least 1 month off treatment each year to see whether she is postmenopausal. Alendronate has not been approved for women who are premenopausal, particularly because of pregnancy. However, if the patient is not pregnant and will not become pregnant, alendronate has been used by numerous centers, either as a low dose for prevention of osteoporosis or high dose for treatment of osteoporosis. To date there is no approved method for bone stimulation and trials of flouride and parathyroid hormone and parathryoid hormone related peptides still are in the experimental stage.

An algorithm is proposed by the National Osteoporosis Foundation (Fig 1) for the treatment of patients who are at risk for having a fracture develop.³⁷ If the individual has a known vertebral fracture, the use of hormone replacement therapy or alendronate or calcitonin would be recommended. If there is no fracture and the patient is not willing to consider treatment, then the recommendations would be calcium, vitamin D, exercise, and smoking cessation. If patients are willing to consider a treatment and are older than 65 years of age, bone density should be measured and treated depending on level of bone loss. If the patient has osteoporosis, he or she should be treated for osteoporosis, and if the patient has osteopenia, he or she should be treated with preventative measures. A bone scan would be indicated if the patient is younger than 65 years of age, has positive risk factors, particularly low body weight, a personal history of fracture or a fracture in their first-degree relatives, or smokes. If the patient does not have risk factors, then calcium, exercise, and smoking cessation should be recommended. As an option, a bone mineral density scan could be taken after menopause.

Fig 1: A diagram for evaluating the patient's risk for fracture is shown. BMD = bone mineral density; HRT = hormone replacement therapy. (Reprinted with permission from National Osteoporosis Foundation: Osteoporosis: Physician's Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ, Excerpta Medica, Inc 1998).

General recommendations made to patients should include physiologic calcium and vitamin D for their age, probably in the order of 400 to 800 units per day. Patients should consider taking estrogen twice in their lifetime, at menopause and at the age of 70 years. Appropriate exercise should be done including impact, strengthening, and balance training. In terms of balance training, effective programs include sports, dancing, and Tai Chi. One study revealed that Tai Chi is the best intervention in preventing falls. A 47% decrease in falls was reported.⁵⁴ In terms of evaluating the status of osteoporosis, the two major elements besides risk factors include a bone density determination of apparent bone mass and a measure of bone markers, notably the collagen breakdown products to show the level of bone turnover. Treatments should be based appropriately. Finally, hip fractures are the major consequence of osteoporosis. Therefore, attempts should be made to prevent osteoporosis and to prevent falls. Clearly, prevention is much better than treatment for osteoporosis. The successful tools for the diagnosis, prevention, and treatment of osteoporosis are now readily available to eliminate this disorder.