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The Journal of Bone and Joint Surgery (American) 78:618-32 (1996)
© 1996 The Journal of Bone and Joint Surgery, Inc.

Instructional Course Lecture

Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Osteoporosis: Diagnosis and Treatment*{dagger}

JOSEPH M. LANE, M.D.{ddagger}, EDWARD H. RILEY, M.D.{ddagger} and PHILIP Z. WIRGANOWICZ, M.D.{ddagger}, LOS ANGELES, CALIFORNIA

An Instructional Course Lecture, The American Academy of Orthopaedic Surgeons


   Introduction
Top
 Introduction
Bone Metabolism
 Bone Biomechanics
 Evaluation of Osteoporosis
 Treatment of Osteoporosis
 Conclusions
 References
 
Osteoporosis is characterized by decreased bone mass and increased susceptibility to fracture. Primary osteoporosis is defined as osteoporosis that occurs in an individual who has no endocrinopathy or other disease state that would account for the changes in bone mass. Osteoporosis affects 20 million individuals in the United States1. These individuals sustain more than 1.2 million fractures (including more than 280,000 fractures of the hip) annually; the estimated cost of treatment of such fractures was $10 billion in 19921,112. The absolute number and percentage of persons who have osteoporosis are expected to increase because of the prolonged longevity of the American population. The risk of a fracture of the proximal part of the femur increases with age, especially in women who are more than fifty years old92. Fractures of the proximal part of the femur are associated with a high rate of mortality, and most persons who have sustained such a fracture never regain their previous level of function72. Emotional morbidity in the form of depression, reclusiveness, and fear of additional fracture may accompany osteoporosis. Advances in our understanding of the etiology and pathophysiology of osteoporosis, as well as progress in the prevention and treatment of this disease, have given the physician the ability to intervene successfully.

Riggs and Melton classified primary osteoporosis on the basis of the patterns of bone loss and fracture111. Postmenopausal (type-I), or osteoclast-mediated, osteoporosis is characterized by rapid bone loss and is seen most often in recently postmenopausal women (it affects women six times more frequently than men). This pattern is consistent with high-turnover osteoporosis. There is a rapid phase of bone loss predominantly involving trabecular bone and an association with vertebral and distal radial fractures.

Senile (type-II), or osteoblast-mediated, osteoporosis affects women twice as frequently as men and is related to aging, chronic calcium deficiency, increased parathyroid hormone activity, and decreased bone formation. An individual can display traits of both types of osteoporosis over time.

Osteoporosis is currently the subject of a major interdisciplinary research effort. Consequently, there is a relatively large diversity of opinion regarding the best approach to the management of the osteoporotic patient. The purpose of the present lecture is to review the pertinent information regarding the biological characteristics, physiology, evaluation, treatment, and prevention of osteoporosis. An attempt has been made to present a middle-of-the-road position on the various issues, leaving room for controversy on either side. Some of the information presented undoubtedly will be altered with additional research.


   Bone Metabolism
Top
 Introduction
 Bone Metabolism
Bone Biomechanics
 Evaluation of Osteoporosis
 Treatment of Osteoporosis
 Conclusions
 References
 
Bone is a living matrix that is in constant flux and under direct cellular control. Bone is formed by osteoblasts, which are cells of marrow stromal origin77,104,115,127. Newly formed bone contains an organic matrix consisting primarily of type-I collagen that has undergone mineralization. Bone resorption is under the control of osteoclasts. These large, multinucleated cells arise from macrophage precursors. They cause bone resorption by first isolating a segment of bone surface, thereby creating a Howship lacuna. Next, acidification solubilizes the mineral phase by means of a carbonic anhydrase mechanism, and, finally, the production of acid proteases allows for the enzymatic degradation of the organic components, including the collagen.

During the process of continued bone formation, the osteoblasts encase themselves within the bone matrix and become osteocytes. The osteocytes have direct connections to the outer bone surface through microcanaliculi, which play a critical role in calcium flux. Frost first described the bone metabolic unit as a coupled process in which resorption precedes formation38. Bone-remodeling proceeds throughout life, and an imbalance in this process that either enhances resorption or impairs formation ultimately leads to a net loss of bone mass. The recent Instructional Course Lecture by Buckwalter et al. provides a more detailed discussion of bone biology11,12.

Calcium
Calcium is an essential mineral that participates in many important physiological functions. Only the attainment of peak bone mass and the maintenance of the skeleton are considered here. Calcium requirements change throughout life depending on the activity and function of the body as well as on the efficiency of intestinal absorption51,52,55,56,96 (Table I). Approximately 25 per cent of the dietary dose of calcium is absorbed, primarily in the upper part of the gut. In young adults, intestinal absorption of calcium is easily accomplished and is the major route by which calcium is provided to the body. In elderly individuals, the intestine is less effective with regard to the absorption of calcium. During periods of negative calcium balance, bone resorption is the principal method of maintaining the serum calcium level. Normal absorption of calcium by the gut requires an appropriate gastric pH, an adequate serum level of 1,25-dihydroxyvitamin D, and an appropriate dietary calcium-phosphate ratio. Inhibitors of calcium absorption in the gut include decreased serum vitamin-D levels; increased dietary phosphates (soft drinks), fat, phytates, and oxalates; sprue and gastrointestinal disorders, such as achlorhydria and blind-loop syndrome; and certain renal disorders. In addition, calcium absorption is compromised by many chronically administered drugs, such as phenytoin, isoniazid, corticosteroids, heparin, tetracycline, and furosemide.


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  		TABLE I DAILY CALCIUM REQUIREMENTS

 
Bone mass increases during childhood, and peak bone mass is obtained by the middle of the third decade86,125,130. Ultimate peak bone mass can be affected adversely by inadequate dietary calcium intake during the years of skeletal growth66. Although appealing, the converse has not been demonstrated consistently, and there probably is a threshold level beyond which additional calcium intake during the years of skeletal growth does not affect beneficially the attainment of peak bone mass. A large proportion of girls and women who are more than thirteen years old do not have adequate calcium intake and, therefore, have a lower potential peak bone mass65,87,107.

The greater the peak bone mass achieved, the better the chance of avoiding osteoporosis later in life. After peak bone mass is reached, bone loss normally occurs at the rate of 0.3 per cent per year in men and 0.5 per cent per year in women. A rate of bone loss of 2 to 3 per cent per year (an 8 per cent decrease in trabecular bone and a 0.5 per cent decrease in cortical bone) begins at the onset of menopause. This rate continues for a period of six to ten years and then declines to a rate of 0.5 per cent per year. While all adults lose bone with age, osteoporosis develops in only 20 to 30 per cent of women and 10 to 20 per cent of men who are more than sixty-five years old23,111.

Calcitropic Hormones
Vitamin D: Many hormones directly affect bone metabolism75. A major one is vitamin D, a sterol hormone that plays a critical role in calcium metabolism. Vitamin D is formed from 7-dehydrocholesterol in the skin under the direct stimulation of ultraviolet light (Fig. 1). The vitamin-D precursor is converted to 25-hydroxyvitamin D in the liver before being activated by further hydroxylation to 1,25-dihydroxyvitamin D in the kidneys in response to parathyroid hormone. 1,25-dihydroxyvitamin D increases absorption of calcium across the gut by maturing the villus lining cells of the intestine and stimulating them to produce calcium-binding protein. Active vitamin D augments parathyroid hormone recruitment of osteoclasts for bone resorption by acting as a maturation hormone for the macrophage stem cell.



Illustration of vitamin-D production and the hormonal regulation in the control and coordination of total body calcium. (Reprinted, with permission, from: Mohler, D. G.; Lane, J. M.; Cole, B. J.; and Weinerman, S. A.: Skeletal failure in osteoporosis. In Diagnosis and Management of Pathologic Fractures, p. 24. Edited by J. M. Lane and J. H. Healey. New York, Raven Press, 1993.)

 
Parathyroid hormone: The second prominent hormone in bone metabolism is parathyroid hormone75. Parathyroid hormone responds to low ionic calcium levels by stimulating the retention of calcium and excretion of phosphate by the kidneys. In addition, parathyroid hormone indirectly increases the absorption of calcium across the gut by stimulating the conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D in the medullary portion of the kidneys. Indirectly, by means of the osteoblast (the coupling factor leading to increased osteoclast activation), parathyroid hormone leads to bone resorption. Hence, parathyroid hormone indirectly leads to the absorption of calcium across the gut, the resorption of calcium from bone, and increased retention of calcium within the kidneys140.

Calcitonin: Calcitonin is a calcitropic peptide produced in the parafollicular cells of the thyroid gland. Calcitonin responds to elevated serum ionic calcium levels by decreasing the number and activity of osteoclasts3. Calcitonin also functions as a neuropeptide and has analgesic effects, as will be discussed. Its pharmacological activity primarily decreases bone resorption and secondarily causes a transient increase in bone formation by means of a still unknown mechanism.

Estrogen: A normal balance of estrogen and progestin is critical for the maintenance of bone mass. Young women who have episodes of amenorrhea or oligomenorrhea before peak bone mass is attained lose 2 per cent of bone mass per year instead of gaining 2 to 4 per cent per year as they would normally. This loss is estrogen-dependent, and the bone mass that is lost is not regained once normal menstrual cycles are resumed13,81,137. The level of circulating estrogen declines after menopause. Some women have a rapid acceleration of bone loss secondary to increased bone-remodeling, with bone resorption exceeding bone formation57. Although estrogen has been shown to inhibit bone resorption, the exact mechanism by which this occurs and why it affects only some individuals remain unclear. There is clear evidence that estrogen receptors are present in osteoblast-like cells31. The presence of such receptors in osteoclasts and the influence of estrogen on those cells have not been discerned.

Glucocorticoids: Glucocorticoids profoundly affect bone metabolism. Exogenously administered corticosteroids impair the function and shorten the lifespan of osteoblasts and contribute to decreased bone formation45. Corticosteroids increase the excretion of calcium in the urine and block the resorption of calcium in the gut. These latter two effects create a relative hypocalcemia that induces secondary hyperparathyroidism. The hyperparathyroidism then leads to osteoclastic bone resorption, which proceeds uncoupled from the aforementioned reduced rate of bone formation48. The result is a form of osteoporosis that is histologically distinct from postmenopausal osteoporosis in that there is markedly enhanced bone resorption and a profound absence of bone formation. The optimum treatment of this form of osteoporosis is different than that for the postmenopausal form. Minimizing the steroid dose is helpful. Spector and Sambrook126 as well as Meunier91 offered additional useful guidelines in the absence of definitive studies.

Thyroid hormone: There have been several reports on the effects of hyperthyroidism and the administration of exogenous thyroid hormone on bone mass28,37,95. Thyroid hormone increases bone-remodeling with osteoclast activity predominating, inducing a net loss of bone95. Untreated hyperthyroidism results in high-turnover osteoporosis, which leads to an increased risk of fracture28. Questions remain as to the effect of physiological replacement of thyroid hormone and its potential for inducing osteoporosis. Men and premenopausal women who receive replacement therapy with the lowest possible dose of thyroxine, with the level of thyroid-stimulating hormone kept in the normal range, probably are not at increased risk for fractures37,83. In contrast, postmenopausal women who receive such replacement therapy have a dose-dependent decrease in bone mineral density and an increased risk of a fracture of the hip7. Estrogen appears to mitigate partially the effects of exogenous thyroid hormone on bone loss120.


   Bone Biomechanics
Top
 Introduction
 Bone Metabolism
 Bone Biomechanics
Evaluation of Osteoporosis
 Treatment of Osteoporosis
 Conclusions
 References
 
Cortical bone has a low ratio of surface area to volume, while trabecular bone proportionately has a much greater surface area. Bone turnover is a surface event, and therefore it affects trabecular bone more profoundly than cortical bone. Consequently, bones and bone regions rich in trabeculae, such as the vertebrae, the calcaneus, and the metaphyseal segments of the long bones, are subject to a loss of structural integrity during the aging process76. The body accommodates for bone loss by redistribution. The diameter of the long bones gradually increases with age in both women and men, and a concurrent increase in the medullary diameter leads to a net thinning of the cortical bone. A shift of 10 per cent of the bone mass outward from the epicenter of the bone through this process of enlargement compensates for a 30 per cent decrease in bone mass when bending and torque stresses are applied to the bone. However, this shift of bone mass provides no such protection when an axial load is applied.

The structural strength of bone is related not only to bone mass and its anatomical distribution but also to a concept known as connectivity. Connectivity refers to the degree of trabecular interconnectedness within bone. Mellish et al.89 and others18,123 demonstrated that osteoporosis involves a thinning of the cortex as well as a change in the structure of trabecular bone. Within trabecular bone, there are areas in which osteoclasts have created a discontinuity of the trabeculae, shifting the structure of the bone from plates to narrow bars and weakening it in that area. Barth and Lane6 as well as Grampp et al.42 reported that as many as three of eight individuals who had an extremely low bone mass in the spine did not sustain vertebral fractures. Thus, the ultimate strength of a specific bone is related to the relative amounts of trabecular and cortical bone, the architectural distribution of the bone mass, and the structural integrity and connectivity of the bone.

Physical Activity
Physical activity is both an important, albeit incompletely understood, factor in bone formation and a common therapeutic intervention. Exercise frequently is prescribed as part of the treatment regimen for patients who have osteoporosis and is recommended for its over-all salutary effects in terms of balance, strength, and flexibility. Impact-loading exercises appear to be effective and site-specific in the maintenance of bone mass82,110. However, cross-sectional population studies have indicated a more positive relationship between exercise and bone mass than have prospective clinical trials29. Selection bias (in that individuals who exercise have greater bone mass than do sedentary individuals) may explain the discrepancies among those studies. The effect of physical activity on peak bone mass is most evident during the years of skeletal growth and is relatively minor in older adults20,80. The rate of bone loss among young women who are amenorrheic as the result of chronically high levels of exercise, however, is substantially greater than that among young women who maintain normal menstrual cycles but do not exercise62.

As a group, women who exercise and maintain normal menstrual cycles have the greatest bone mass. Eumenorrheic women who do not exercise have less bone mass, and amenorrheic women who exercise have the least. The presumed etiology of the amenorrhea in women who exercise is an inadequate caloric intake81. This presumption is supported by the finding that amenorrheic women do not respond to cyclical administration of hormones unless they also gain weight13,137. In addition, male marathon runners who have inadequate caloric intake also have low bone mass despite having a normal level of testosterone59.

The constellation of disordered eating, amenorrhea, and osteoporosis has been recognized as a serious threat to the health of the female athlete and has been termed the female triad36. This triad predisposes the athlete to multiple fractures and other medical problems. Athletes who participate in gymnastics, diving, figure skating, dance, track, and synchronized swimming are affected most frequently36. When this triad is identified, the patient should reduce or modify her training regimen, increase caloric and calcium intake, and consider cyclical estrogen and progestin therapy.


   Evaluation of Osteoporosis
Top
 Introduction
 Bone Metabolism
 Bone Biomechanics
 Evaluation of Osteoporosis
Treatment of Osteoporosis
 Conclusions
 References
 
The evaluation of a patient in whom osteoporosis is suspected should include a thorough medical history, imaging and laboratory studies, and possibly bone histomorphometry. Common fractures due to osteoporosis include wedge fractures of the thoracic spine; central end-plate cupping of the lordotic lumbar vertebral body; and fractures of the proximal and supracondylar regions of the femur as well as of the tibial plateau, the humeral neck, and the distal part of the radius (Figs. 2 and 3). The workup of a patient who has sustained an insufficiency fracture (a fracture that was not the result of noticeable trauma) should proceed in a logical fashion. The possibility of a bone tumor should be evaluated with use of plain radiography, magnetic resonance imaging, computerized tomography, or bone-scanning. An endocrinopathy or osteomalacia should be ruled out with appropriate laboratory tests (Fig. 4).



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  		Lateral radiograph of the chest of a patient who had severe osteoporosis, showing kyphosis due to multiple vertebral wedge fractures.

 


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  		Anteroposterior radiograph of the proximal part of the femur of a patient who had osteoporosis, showing a fracture of the femoral neck.

 


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  		Workup for an insufficiency fracture.

 

History

Risks for Osteoporosis
If the patient has a fracture that was not due to noticeable trauma, the clinician first must rule out the presence of a benign, metastatic, or primary malignant bone tumor. Once a tumor has been excluded, the major causes of such a fracture include bone-marrow abnormalities, endocrinopathies, osteomalacia, and osteoporosis.

Risk factors for osteoporosis that the clinician should seek to identify include early natural or operatively induced menopause, prolonged periods of amenorrhea, poor nutrition, a history of limited exercise, genetic factors (a positive family history), and a history of excessive alcohol intake or smoking. Healey and Lane49 reported that twenty-seven (57 per cent) of forty-seven women with osteoporosis had scoliosis of at least 10 degrees. Velis et al.135,136 and Healey and Lane49 demonstrated that all women who have scoliosis, regardless of whether they are premenopausal or postmenopausal, have lower bone mass than their peers.

Risks for Falls
In addition to assessing the risk factors for osteoporosis, the clinician must evaluate the patient's risk of falling. More than 90 per cent of fractures of the hip are associated with falls26,44. Fractures of the proximal part of the femur resulting from falls are due to the interaction of three factors: the strength of the bone, the severity of the fall, and the tendency of the patient to fall. While osteoporosis per se is responsible only for a decrease in bone strength, femoral fractures due to falls account for the preponderance of the morbidity associated with osteoporosis.

Cummings et al.24, in a prospective study, found that the risk of a fracture of the proximal part of the femur increased with every five years of aging and that an increased risk was associated with a maternal history of a fracture of the hip, tall height, lack of weight gain with aging, poor health, previously treated hyperthyroidism, the use of anticonvulsants or long-acting benzodiazepines, the lack of walking for exercise, the lack of unsupported standing for four hours a day, a pulse rate of more than eighty beats per minute with the patient at rest, a history of any fracture since the age of fifty years, the consumption of caffeine, poor visual depth perception, the inability to rise from a chair without using the arms, and a low bone mass. Those authors reported that if an individual had as many as two of these risk factors, the risk of a fracture of the hip was one per 1000 patients per year. If the patient had five risk factors or more in addition to the risk factor of low bone mass, the risk of a fracture of the hip increased to twenty-seven per 1000 patients per year. Greenspan et al.43 also documented that causative factors for these fractures include falls on the side, diminished bone density, a lower bone-mass index, and a higher potential energy of fall.

Courtney et al.21 showed that the femur of an elderly individual has one-half the strength and one-third the energy-absorption capacity of that of a younger individual. This finding indicates that the proximal part of the femur of elderly individuals is at risk for fractures due to simple falls. Simulated falls from a standing height directly onto the greater trochanter generated an impact force that exceeded femoral strength by 50 per cent in specimens from elderly individuals but was approximately 20 per cent less than femoral strength in specimens from younger individuals21. Factors that increase the risk of a fracture due to a fall include impact on or near the greater trochanter; the lack of protective mechanisms, such as the use of an outstretched arm, to break the fall; and insufficient energy absorption by the local soft tissues22. On the basis of a thorough history, the physician can make recommendations to reduce the chances of the patient falling and sustaining a fracture of the hip. Recommendations may include the removal of environmental hazards such as throw rugs and poor lighting, caution with regard to the use of sedatives, a regular program of exercise, and balance training. Prospective trials are under way to determine if trochanteric padding or energy-absorbent floors can be recommended to reduce the prevalence of fractures of the hip in susceptible populations.

Imaging Studies and the Measurement of Bone Mineral Density
The primary goal in the treatment of osteoporosis is to prevent bone loss beyond the fracture threshold. Measurements of bone mineral density can be used to assess the risk of a fracture with a high degree of specificity141. There is a 1.5 to threefold increase in the fracture rate for each standard deviation of decrease in bone mineral density25,61. Thus, if the average remaining lifetime risk of a fracture is 15 per cent in a group of fifty-year-old women who have average bone-mineral density, then the lifetime risk of a fracture is approximately 30 per cent for a fifty-year-old woman in whom the bone mineral density is one standard deviation less than the average and approximately 60 per cent for a fifty-year-old woman in whom the bone mineral density is two standard deviations less than the average67.

Although the risk of a fracture increases continuously as bone mineral density declines, it is useful, from a practical standpoint, to define cutoff values for the purpose of intervention. Defining osteoporosis as a bone mineral density of 2.5 standard deviations less than the average value for young adults identifies approximately 30 per cent of postmenopausal women who are at the highest risk for a fracture and who need corresponding counseling and treatment67. Defining an additional cutoff value as one standard deviation less than the average value for young adults creates another group that includes approximately 15 per cent of postmenopausal women in whom the prevention of bone loss would be most useful as well.

Bone mass can be determined with a number of non-invasive methods42,63. The critical elements of any system include precision, accuracy, and sensitivity to changes in bone mass. Radiographs of the spine demonstrate osteopenia (a radiographic term for an apparent decrease in bone mass density) only when 30 per cent of the bone mass has been lost. The preferential loss of horizontal trabeculae in the vertebral body gives the remaining vertical trabeculae a hypertrophic appearance.

Determination of precisely when a vertebral deformation that is due to osteoporosis constitutes a fracture can be difficult with use of standard radiographic techniques. The lack of a universally accepted definition of a fracture has serious implications; as the definition is expanded to include more minor changes, the specific effect of any drug intervention on the disease process becomes more difficult to assess. Genant et al.129,138 required a 25 per cent change in one dimension or a 40 per cent change in the total cross-sectional area as the minimum criterion for a vertebral fracture.

Single-beam densitometry can be used to measure bone mass at the distal third of the forearm69. Although the extreme distal end of the radius, termed the ultradistal radius, is more sensitive to changes, reproducibility of results is difficult to achieve at that location69. The cortical bone of the distal third of the radius is not very sensitive to changes in bone metabolism, and the findings at that location may not correspond with the changes in the spine or the hip.

Quantitative computed-tomography scanning can be used to examine a window within the vertebral body as well as to measure the trabecular bone mass therein. Among radiographic methods, it is the most sensitive to changes in bone mass; however, it is less precise, is more costly, and results in a higher exposure to radiation than dual-energy x-ray absorptiometry50,121. Therefore, quantitative computed tomography generally is reserved for research studies.

Dual-energy x-ray absorptiometry, commonly called DEXA, has a high rate of precision and subjects the patient to an extremely low dose of radiation; it is currently the most frequently used method of evaluating bone density in clinical practice50,88,121.

Laboratory Studies
Laboratory studies are used to exclude other diseases that can cause osteopenia and to determine the type of osteoporosis93. As indicated in the algorithm for the workup of a patient who has an insufficiency fracture (Fig. 4), a complete blood-cell count with differential, determination of the erythrocyte sedimentation rate, and immunoelectrophoresis identify most bone-marrow abnormalities. Such abnormalities are seen in approximately 2 per cent of patients who have osteopenia, and half of these abnormalities are multiple myeloma75. If such an abnormality is suspected, a bone-marrow aspiration is performed. If no bone-marrow abnormality is noted, common endocrinopathies are sought. Initially, one should screen for hyperparathyroidism and hyperthyroidism by measuring serum levels of parathyroid hormone and thyroid-stimulating hormone by radioimmunoassay. Corticosteroid-induced osteoporosis, Cushing disease, and diabetes mellitus are sought if they are suspected clinically.

Once endocrinopathies have been excluded, as many as 10 per cent of older individuals who live in northern communities in the United States and who have osteopenia will be found to have varying levels of osteomalacia75,76. Osteomalacia can be diagnosed, in more than 50 per cent of these individuals, on the basis of simple blood tests that show low-normal serum calcium levels, low phosphate and 25-hydroxyvitamin-D levels, and high alkaline phosphatase and parathyroid hormone levels. More subtle forms of osteomalacia are more difficult to diagnose and may necessitate bone biopsy75.

Advances in the understanding of metabolic bone disease have led to the development of more specific laboratory tests105,119. Bone-specific alkaline phosphatase, osteocalcin, and procollagen-I extension propeptides specifically reflect bone formation. Markers of bone degradation are more non-specific, but urinary pyridinoline and deoxypyridinoline correspond well with histological indices of bone resorption. These tests can be helpful in complicated cases and in identifying the types of osteoporosis that are difficult to diagnose.

Bone Histomorphometry
Although the more advanced laboratory tests that screen for the presence of markers of bone formation and degradation in blood and urine accurately reflect the metabolic activity of bone in most patients, the determination of bone mass does not characterize the qualitative status of the bone93,134. Other methods of assessing the quality of bone are therefore necessary.

A biopsy of tetracycline-labeled, undecalcified, iliac-crest bone is the best method of differentiating among high-turnover and low-turnover osteoporosis, osteomalacia, secondary hyperparathyroidism, and complicated combinations of these conditions. The recent chapter by Mohler et al. provides additional information93.

The current candidates for bone biopsy at the University of California at Los Angeles Osteoporosis Center are individuals who are less than sixty years old and in whom bone density is at least 2.5 standard deviations less than that of their peers; individuals who are less than sixty-five years old, who do not have an apparent metabolic abnormality, and who have sustained a low-energy fracture; and patients who are being managed with chemotherapy, antimetabolites, or corticosteroids because of complex medical problems.


   Treatment of Osteoporosis
Top
 Introduction
 Bone Metabolism
 Bone Biomechanics
 Evaluation of Osteoporosis
 Treatment of Osteoporosis
Conclusions
 References
 

Pharmacological Therapy

Calcium
Calcium is one of the most widely used agents in the treatment of osteoporosis53,54. Since most children have an inadequate calcium intake, the peak bone mass achieved is often less than it might have been. This creates a major risk for osteoporosis later in life51-55. Girls at puberty are probably the optimum population for the early use of calcium to prevent osteoporosis84. There is, however, a level of calcium intake beyond which additional supplementation yields no greater ultimate peak bone density. Matkovic and Heaney85 pointed out that the administration of calcium supplements during growth may only accelerate the attainment of peak bone mass and that there is no evidence that it increases the actual peak bone mass ultimately achieved.

Calcium supplementation does not appear to decrease the 10 per cent loss of bone mass that occurs in the spine during the first several years after menopause, but it is helpful at all ages in enhancing appendicular bone mass75-77,93. Calcium supplementation in the older population may be most effective when the baseline calcium intake is less than 400 milligrams per day, for those who have an intestinal malabsorption syndrome, or in combination with an exercise regimen27. Calcium supplementation is helpful for patients who have type-II osteoporosis, especially when the therapy is combined with vitamin-D supplementation14,112.

A marked decrease in the rate of fractures of the hip was demonstrated in a study14 of elderly patients from France who had received dietary supplements of calcium and vitamin D. This decrease occurred even though little difference was noted in bone mass, a finding that raises the possibility that the calcium and vitamin-D supplementation had improved the quality of bone or had decreased the prevalence of secondary hyperparathyroidism.

Vitamin D
Vitamin-D deficiency is common in elderly individuals who have osteoporosis, in strict vegetarians, and in populations of some northern locations during the winter73,74,97. Individuals who have vitamin-D deficiency typically have poor calcium absorption as well. Vitamin D stimulates bone formation and intestinal calcium absorption; vitamin-D supplementation therefore may improve calcium balance. In addition, vitamin D may positively influence bone density in healthy individuals who do not have vitamin-D deficiency or osteoporosis by suppressing parathyroid hormone activity14,70. This may be especially important during the winter months, during which lower levels of vitamin D and higher levels of parathyroid hormone have been shown to coincide with an increased prevalence of osteoporotic fractures70,93. Subjects who had been given a single high dose (100,000 units) of vitamin D in early winter had higher serum vitamin-D concentrations and lower parathyroid hormone levels than did controls after five weeks70. Several recent studies have shown that the oral administration of calcitriol and some of its synthetic precursors, notably alfacalcidol (1-alpha-hydroxyvitamin D3), can correct mild secondary hyperparathyroidism, reduce bone loss, and prevent fractures of the hip90,98,131.

Receptors of vitamin D on the osteoblast display phenotypic heterogeneity. This genetic variability was investigated in Australia in an attempt to explain the low levels of vitamin D in individuals who have osteoporosis and the generally positive but inconsistent responses of such individuals to therapy94. Additional work in this area may lead to genetic tests for a predisposition to low bone density and allow for the development of more tailored prophylactic interventions94. Unfortunately, these results have not been seen consistently in other countries, and the polymorphism of the receptor sites is still under study.

Estrogen
Estrogen deficiency plays a prominent role in the pathogenesis of osteoporosis. Estrogen inhibits bone resorption and positively affects calcium balance, either directly, by stimulating the estrogen receptors in bone, or indirectly, by suppressing the production of bone-resorbing cytokines41,64,100,101. With few exceptions, estrogen therapy protects against postmenopausal osteoporosis regardless of which form of estrogen is administered or which technique is used to measure bone density139. The administration of estrogen to postmenopausal women not only prevents bone loss but also protects against vertebral and femoral fractures, with a greater effect on the spine33,71,75,79,93. Discontinuation of the therapy is followed by an immediate resumption of bone loss at a rate similar to that in women who have not received such therapy15.

Several different estrogen regimens are available for the treatment of postmenopausal osteoporosis5,19,78. The use of estrogen therapy is increasing worldwide, but even in the countries in which it is used most extensively, no more than one-third of the women accept it over the long term19. This situation is the result of side effects, primarily endometrial bleeding, and concern by the public and among physicians about the relative risks of cardiovascular disease as well as endometrial and breast cancer2,58. Prolonged use of estrogen appears to increase the risk of breast cancer by 30 per cent8,16,17, an increase roughly from eleven to fourteen instances of breast cancer per 100 women. It is important to note that women in whom breast cancer develops during the course of estrogen therapy do not appear to have an increased rate of mortality8,17. Therefore, women should have regular gynecological and breast examinations, including mammography, while receiving estrogen therapy. The concomitant administration of progestin eliminates the risk of uterine cancer, and continuous therapy with a combination of progestin and estrogen can minimize cyclical uterine bleeding in older women122. Most of the cardiovascular benefits associated with estrogen are preserved when progestin is given cyclically, but the continuous use of progestin diminishes some of the cardiovascular benefits of estrogen.

Estrogen is an ideal agent for patients who have a high risk of cardiovascular disease, no family history of early breast cancer, a strong family history of osteoporosis or a low bone-mineral density, and substantial postmenopausal symptoms and who are receiving thyroid hormone-replacement therapy. Conversely, patients who do not have osteoporosis or coronary artery disease or substantial risk factors for these diseases, or who have a history of thrombophlebitis or a family history of early breast cancer, are considered poor candidates for estrogen supplementation. The usual daily dose of estrogen required to prevent bone loss is 0.625 milligram, but half of this dose may suffice when it is combined with calcium supplementation122.

There is an increasing recognition that estrogen therapy may have to be adjusted to the individual patient. About 20 per cent of women who receive conventional doses of estrogen continue to lose bone mass117, and such patients might benefit from a higher dose. Women who smoke may need a higher dose because of an increased rate of estrogen degradation60. Conversely, obese women who produce substantial amounts of estrogen peripherally may need a lower dose133. The use of estrogen during only the early (six to ten-year) postmenopausal period appears to be inadequate32. A study of older women from the Framingham observational group showed that the previous use of estrogen was not protective against fractures of the hip that occurred ten to twenty years after the termination of treatment35. Only use of estrogen for more than seven years was found to be protective35. Some researchers have suggested that estrogen therapy should not be initiated until the patient is sixty-five years old because prolonged use increases the risk of breast cancer16. This approach, however, is unlikely to gain wide acceptance.

Calcitonin
Calcitonin can be used to treat osteoporosis, although patients who have osteoporosis do not appear to have a deficiency of this hormone9. Calcitonin is used commonly in some countries for the short-term amelioration of pain associated with fractures due to osteoporosis because it has an analgesic property, as a result either of elevating the level of endorphins or of inhibiting the release of neuropeptides40. It binds to specific receptors on the osteoclast and exerts an inhibitory effect on its activity. Trabecular bone is affected, but cortical bone is not. Calcitonin has been shown to be a safe alternative for the treatment of osteoporosis in women who cannot take estrogen72. Women who have high-turnover osteoporosis or who have pain because of a recent vertebral fracture are likely to benefit most from its use.

Calcitonin typically is administered by means of subcutaneous injection and also has been shown to be effective in intranasal, rectal, and transdermal forms, although there may be erratic patterns of absorption with the nasal route. The analgesic effects of the newly released nasal form are similar to those of the other forms. Reginster et al.109 conducted a three-year randomized placebo-controlled study in which women in whom menopause had taken place six to thirty-six months previously were given either calcium alone or the same amount of calcium in addition to calcitonin by means of nasal administration. Lumbar bone-mineral density increased slightly (1.8 ± 5.7 per cent [average and standard deviation]) in the women receiving calcitonin and calcium. In those receiving calcium alone, lumbar bone-mineral density decreased 5.8 ± 4.8 per cent. An evaluation performed at five years revealed that the bone mineral density had remained significantly greater (p < 0.001) in the patients who had been managed with calcitonin108.

Bisphosphonates
Bisphosphonates are stable, active analogs of pyrophosphate that both inhibit osteoclastic resorption and depress bone turnover30,118,124. Etidronate has been used for many years for the treatment of Paget disease, but it has not been approved by the Food and Drug Administration for the treatment of osteoporosis. Long-term etidronate therapy creates untoward histological changes in bone; such abnormalities may be eliminated by intermittent, cyclical use128. Etidronate and newer bisphosphonates, including alendronate, pamidronate, residronate, taludrinate, and clonodrate, currently are the most extensively investigated agents in osteoporosis research99. Etidronate is most effective during the first two years of therapy46. Bisphosphonates appear to be effective in the five-year period of rapid bone turnover that occurs after menopause. Similar to calcitonin, however, bisphosphonates primarily act on trabecular bone and are less effective in preventing the loss of compact bone as well as fractures of the hip129.

The second-generation agents are more potent and yet cause less inhibition of mineralization than etidronate. These agents appear to have positive effects on vertebral and femoral-neck bone-mineral density132. Alendronate, recently approved by the Food and Drug Administration, appears to prevent vertebral bone loss in patients who have osteoporosis and does not alter the mechanical properties of bone4. In addition, it appears to continue to work even after it is no longer being administered. Rossini et al.116 recently reported that lumbar bone-mineral density increased by 3.7 ± 1.7 per cent (average and standard deviation) after six months of alendronate therapy and did not change six and twelve months after the cessation of treatment.

Fluoride
In contrast to the antiresorptive drugs described previously, fluoride causes osteoblast proliferation and stimulates new bone formation. Researchers have found substantial increases in trabecular bone in patients who had received fluoride10,34. Enthusiasm for fluoride has been tempered by studies that have shown impaired bone mineralization and increased rates of fractures of the hip and vertebrae despite increased bone density in the lumbar spine113,114.

Early clinical trials involved the administration of high doses of fluoride (more than seventy-five milligrams per day)113. Analysis of patients who sustained fractures of the hip during the course of fluoride treatment revealed that the patients had been receiving excessive doses of fluoride; patients who had high-turnover osteoporosis were not excluded from that study75. Patients in whom osteoporosis is treated with fluoride often have a calcium deficiency because of the increased mineralization of trabecular bone. This situation renders the patients vulnerable to secondary hyperparathyroidism. Vitamin-D supplementation can correct the calcium deficiency while potentiating the effect of fluoride on the osteoblast; this allows the dose of fluoride to be decreased and thereby minimizes its side effects68.

Proponents of fluoride use suggest that better results are possible with lower doses (approximately fifty milligrams per day) in a delayed-release form103,114. Riggs et al.114 reviewed their original study113, in which high doses of fluoride had been used. A subset of patients from that study were managed with a lower dose of fluoride to avoid side effects. Analysis of the rate of vertebral fractures revealed a complex relationship between bone mineral density and the serum fluoride level. The rate of vertebral fractures decreased as the bone mineral density increased, except when the higher bone-mineral density was associated with a rapid rate of increase of bone mineral density in the spine or a large increase in the level of serum fluoride from baseline. These findings imply that bone formation due to fluoride therapy decreases the rate of vertebral fractures as long as bone production proceeds slowly enough to allow for proper mineralization and as long as the fluoride level does not exceed a toxic threshold.

Pak et al.102 recently reported that patients in whom postmenopausal osteoporosis had been treated with a preparation of slow-release sodium fluoride had a lower rate of vertebral fractures and a higher fracture-free rate (defined as the absence of fractures during the trial) compared with a group of controls who had received calcium. A substantial increase in the bone mass of the lumbar vertebrae of 4 to 5 per cent per year for four years, an average increase in the bone density of the femoral neck of 2.4 per cent per year, and no change in the bone density of the radial shaft were observed in the patients who had received fluoride. The frequency with which minor side effects and appendicular fractures occurred was similar in the two groups. Pak et al. concluded that slow-release sodium fluoride and calcium citrate administered for four years inhibits new vertebral fractures, augments spinal and femoral-neck bone mass, and is safe to use.

The ideal role of fluoride in the future may be to augment bone density at the initiation of therapy before switching to antiresorptive agents for the long-term maintenance of bone density. At the present time, however, the use of fluoride is considered experimental.

Our current treatment protocol for osteoporosis in women at the University of California at Los Angeles Osteoporosis Center involves the separation of premenopausal and postmenopausal patients into two groups (Table II). Premenopausal women who are eumenorrheic should have a physiological calcium intake (700 to 1300 milligrams per day), vitamin-D supplementation (400 international units per day), and appropriate exercise. Premenopausal women who are amenorrheic should be managed as just described and should also consider cyclical estrogen and progestin therapy and have an appropriate caloric intake. All postmenopausal women should have a calcium intake of 1500 milligrams per day and vitamin-D supplementation of 400 international units per day. Postmenopausal women are subdivided according to their bone mineral density. For women who have a bone mineral density that is within one standard deviation less than that of their peers, cyclical estrogen and progestin supplementation should be considered. Women who have a bone mineral density that is one to 2.5 standard deviations less than that of their peers, who do not have a fracture, and who are less than seventy years old should receive estrogen (0.625 milligram per day) and progestin (2.5 to 10.0 milligrams per day). Women who have a fracture or a bone mineral density that is more than 2.5 standard deviations less than that of their peers should receive calcitonin (fifty to 100 units subcutaneously, three to seven days per week) acutely, for as long as eighteen months, in addition to calcium and vitamin-D supplements. Once the administration of calcitonin is discontinued, either estrogen and progestin (if the patient is less than seventy years old) or alendronate (10.0 milligrams per day if the bone mineral density is more than 2.5 standard deviations less than that of the patient's peers) should be given.


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  		TABLE II OSTEOPOROSIS TREATMENT PROTOCOL

 


   Conclusions
Top
 Introduction
 Bone Metabolism
 Bone Biomechanics
 Evaluation of Osteoporosis
 Treatment of Osteoporosis
 Conclusions
References
 
A review of the treatment of osteoporosis indicates that, at the present time, prevention is clearly the best solution. Maximization of peak bone mass and reduction of postmenopausal and age-associated bone loss are both crucial. Adequate calcium intake during growth as well as calcium and vitamin-D supplementation postmenopausally constitute the fundamental strategy applicable to essentially all patients. A lifetime habit of physical exercise and the elimination of falls as well as attenuation of the severity of falls are important for the elderly. Estrogen is the drug of choice for the prevention of postmenopausal bone loss. Calcitonin is the agent of choice for patients who cannot take estrogen or who have pain due to a fracture. The newly approved bisphosphonate, alendronate, appears to have substantial antiresorptive properties with minimum side effects. Fluoride has been shown to affect bone formation positively and may have a role in treatment in the future.


   Footnotes
 
*Printed with permission of The American Academy of Orthopaedic Surgeons. This article will appear in Instructional Course Lectures, Volume 46, The American Academy of Orthopaedic Surgeons, Rosemont, Illinois, March 1997.

{dagger}No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

{ddagger}Department of Orthopaedic Surgery, Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, California 90095.


   References
Top
 Introduction
 Bone Metabolism
 Bone Biomechanics
 Evaluation of Osteoporosis
 Treatment of Osteoporosis
 Conclusions
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