Osteoporosis: Clinical Features, Prevention, and Treatment LAWRENCEA. FLEMING, MD, MBA BONE LOSS is a c o n s e q u e n c e of m e n o p a u s e in w o m e n and of aging in w o m e n and men. Chronologic age is the most p o w e r f u l p r e d i c t o r of b o n e mass; most elderly w o m e n have lost e n o u g h b o n e mass so that they are at risk for fractures. Additionally, individuals w h o reach a p e a k b o n e mass that is relatively l o w or those w h o have additional b o n e loss related to factors other than menopause or aging may e x p e r i e n c e a decline in b o n e mass to levels that are b e l o w "fracture t h r e s h o l d . " The result is a skeleton that is insufficient for mechanical support, a skeleton that fractures easily. The focus for the clinician and patient should be on prevention. Preventive interventions include maximizing the p e a k b o n e mass, minimizing the inevitable b o n e loss that occurs w i t h m e n o p a u s e and aging, reducing individual e x p o s u r e to additional factors that accelerate b o n e loss, and educating the elderly and their caregivers in a p p r o a c h e s to decrease the likelihood of falls. If p r e v e n t i o n fails, s y m p t o m a t i c osteoporosis is managed w i t h antiresorptive therapies that slow b o n e loss or formation-stimulating therapies that p r o m o t e n e w b o n e growth. Osteoporosis is defined as loss of b o n e mass to a level no longer adequate for mechanical support; b o n e mass is the major d e t e r m i n a n t of strength, a c c o u n t i n g for 75 - 85% of the variance in b o n e strength. 1 The cons e q u e n c e of the b o n e loss is an increased susceptibility to fractures, particularly of vertebral bodies, the distal radius, and the p r o x i m a l femur. Bone loss results from an imbalance of resorption and formation in b o n e remodeling; the remaining b o n e has r e d u c e d mass b u t a normal composition. Osteoporosis, the most c o m m o n metabolic b o n e disease, occurs as a primary disorder or is secondary to e n d o c r i n e abnormalities, gastrointestinal diseases, malignancies, connective tissue disorders, or the use of t h e r a p e u t i c agents (Table 1). The emphasis of this rev i e w is p r i m a r y involutional osteoporosis.

EPIDEMIOLOGY Bone loss occurs universally w i t h aging. As populations age, the p r e v a l e n c e of o s t e o p o r o t i c fractures increases. Annually, in the United States, there are an estimated 6 5 0 , 0 0 0 vertebral fractures, 2 5 0 , 0 0 0 hip Received from the Section of General Internal Medicine, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin. Address correspondence and reprint requests to Dr. Fleming: Section of General Internal Medicine, Room J5/223, University Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792.

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fractures, 2 0 0 , 0 0 0 distal forearm fractures, and 4 0 0 , 0 0 0 fractures at other sites attributable to osteoporosis. A 50-year-old w o m a n has a 16% risk of a hip fracture, a 15% risk of a distal radius (Colles') fracture, and a 32% risk of a vertebral fracture in her remaining lifetime 2 The direct and indirect costs of o s t e o p o r o t i c fractures are estimated to b e $ 8 - 10 billion annually. 3 O s t e o p o r o t i c vertebral fractures are not usually associated w i t h a specific external trauma b u t most often result from c o m p r e s s i v e loading such as lifting; they m a y be precipitated b y stresses c o m m o n in the activities of daily living as m i n o r as coughing or sneezing. There are clear relationships b e t w e e n vertebral fracture prevalence, age, and b o n e density. In a r a n d o m sample of Rochester, Minnesota, w o m e n , the estimated incidence of n e w vertebral fractures rose w i t h age and reached 29.6 per 1,000 person-years in w o m e n aged 85 years or older. Similarly, the p r e v a l e n c e of one or m o r e vertebral fractures increased w i t h declining b o n e mass and reached 42% in w o m e n w i t h spinal b o n e density less than 0.6 g / c m 2 b y dual-photon a b s o r p t i o m e t r y (DPA) .4 Two clinical patterns of vertebral o s t e o p o r o t i c c o m p r e s s i o n fractures occur. Fractures in w o m e n in the ten to 15 years after m e n o p a u s e usually have extensive c o m p r e s s i o n and severe pain, whereas vertebral fractures in the elderly, b o t h m e n and w o m e n , are often painless, and recognized later, only incidently on chest or spine films. Population-based studies have s h o w n that the incid e n c e of hip fractures rises as b o n e density in the proximal f e m u r declines. 5 Most hip fractures result f r o m only moderate trauma such as a fall f r o m standing height with i m p a i r e d ability to break the fall. Falls in the elderly are due to the additive effects of factors intrinsic to the patient, factors related to the activity at the time of the fall, and environmental factors. 6 One p e r c e n t of falls in the elderly result in hip fractures. An adult w h i t e w o m a n w i t h a life e x p e c t a n c y of 80 years has a 16% lifetime risk of sustaining a hip fracture, whereas an adult w h i t e male w i t h a life e x p e c t a n c y o f 75 years has a 5% lifetime risk of hip fracture. The mortality in the first year after a hip fracture is 1 2 200/6. 7 Factors important in predicting mortality are serious coexisting illnesses and delirium at the time of hospitalization for the fracture, s More than 50% of hip fracture survivors w h o w e r e previously functionally ind e p e n d e n t will require p e r m a n e n t a m b u l a t i o n assistance because of residual disability. Distal forearm fractures are the most c o m m o n nonvertebral fractures in w h i t e w o m e n until age 75. Like

JOURNALOFGENERALINTERNALMEDICINE,Volume 7 (September/October), 1992

hip fractures, they are most frequently caused by standing-height falls; the radial fracture is a result of an att e m p t to break the fall w i t h an outstretched arm. Forearm fractures rarely have long-term morbidity.

NATURAL COURSE OF BONE FORMATION AND LOSS T w o types of b o n e structure make u p the adult s k e l e t o n - - cortical or c o m p a c t b o n e and trabecular or m e d u l l a r y bone. Cortical b o n e forms the outside surface of all bones and the shafts of the long b o n e s of the a p p e n d i c u l a r skeleton. Trabecular b o n e is a network of plates and rods that are continuous with the inner b o n e cortex and form marrow-containing spaces. Trabecular is the p r e d o m i n a n t b o n e type in the axial skeleton, in the flat bones, and in the ends of the long bones. T h r o u g h childhood, adolescence, and early adulth o o d b o n e mass increases until it peaks at age 30 - 35. G e n d e r and race are determinants of p e a k b o n e mass, w i t h m e n achieving a p e a k mass 30% higher than do w o m e n and blacks achieving a p e a k mass 10% higher than do whites. During the b o n e formation and consolidation years, nutrition, exercise level, and alcohol and tobacco use influence the ultimate p e a k b o n e mass. Later in life, w h e n age-related b o n e loss occurs, those individuals w h o attained a high p e a k b o n e mass are less likely to d e v e l o p s y m p t o m a t i c osteoporosis than are those individuals w h o attained a p e a k b o n e mass that was low. Bone r e m o d e l i n g occurs constantly; at any given time, 10% of the normal skeleton is undergoing remodeling. The r e m o d e l i n g process begins w i t h retraction of flattened cells that line the b o n e surface. Osteoclast precursors migrate to the e x p o s e d b o n e surfaces, w h e r e they fuse into mature osteoclasts that construct resorption cavities. After several weeks, the osteoclasts are replaced by osteoblasts, w h i c h fill the resorption cavities w i t h n e w osteoid for s u b s e q u e n t mineralization. If b o n e mass is to remain constant, there must be a balance b e t w e e n resorption and formation; b o n e loss occurs w h e n there is a net resorption. Net resorption may result from an overactivation of osteoclasts w i t h m o r e and larger resorption cavities than can be filled b y normal osteoblast function, or net resorption may result f r o m normal osteoclast activity with decreased osteoblast function that is not sufficient to fill normal cavities. 9 After a c h i e v e m e n t of p e a k b o n e mass at a b o u t age 35, b o n e mass is stable for the next five years. In b o t h sexes, there is an age-related b o n e loss that begins at age 40; in w o m e n there is an accelerated loss, secondary to estrogen deficiency, that begins at m e n o p a u s e 1° (Fig. 1). In the population, there are sporadically occurring factors (in addition to aging and m e n o p a u s e ) that cause s o m e individuals to e x p e r i e n c e additional b o n e loss. Over their lifetimes, w o m e n lose u p to 50% of trabecular b o n e mass and u p to 35% of cortical b o n e

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TABLE 1 Classificationof Osteoporosis Primary Juvenile Idiopathic Involutional Type 1(postmenopausal) Type 11(age-related) Secondary Endocrine abnormalities Glucocorticoid excess Hypogonadism Hyperparathyroidism Hyperthyroidism Gastrointestinaldiseases Maiabsorption syndromes Primary biliary cirrhosis Lactase deficiency Malignancies Multiple myeloma Disseminatedcarcinoma Connective tissue disorders Osteogenesisimperfecta Homocystinuria Ehlers-Danlossyndrome Rheumatoid arthritis Therapeutic agents Anticonvulsants Long-term heparin therapy Miscellaneous Immobolization Chronic obstructive pulmonary disease Alcoholism

mass; m e n lose 25% of trabecular mass and 25% of cortical mass. Riggs and Melton 11 have suggested an algebraic m o d e l for b o n e density and loss: y = I -- (a~t~ + a2t2 + a3t3) w h e r e y represents the b o n e density at any point in time; 1 represents the peak b o n e density attained; al, a2, a 3 represent rates of b o n e loss over times tl, t2, and t~. The e l e m e n t alt~ represents b o n e loss due to age-related e n d o g e n o u s factors that o c c u r in all individuals. The e l e m e n t a2t2 represents m e n o p a u s e - r e l a t e d b o n e loss, and the e l e m e n t a3t 3 represents b o n e loss due to factors occurring sporadically in the p o p u l a t i o n , such as steroid administration or hyperthyroidism.

Age-related Bone Loss Bone loss occurs with aging; the most p o w e r f u l p r e d i c t o r of b o n e density is chronologic age. In b o t h m e n and w o m e n , the b o n e loss of aging begins at about age 40. Age-related b o n e loss affects trabecular and cortical b o n e equally. As w i t h all net b o n e loss, there is an imbalance b e t w e e n resorption and formation in b o n e - r e m o d e l i n g units. Osteoclasts create normal re-

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ficiency are decreased dietary intake of the vitamin, decreased conversion to the active metabolite, and decreased skin synthesis of vitamin D due to lack of exposure to the sun in the housebound elderly in northern latitudes. ]4

t

~-'len

o r~

Women

I

35 Age RGURE I. Bonelossoccurswith age and menopause.Men attain a maximum bonedensitythat is 30% higherthan the maximum density for women. Women experienceacceleratedtrabecular bone loss in the first 5 - 1 0 years of menopause.Source: Riggs BL. Overviewof osteoporosis. West J Med. 1991; 154:63-77.

sorption cavities but there is subsequent failure of osteoblasts to adequately fill these cavities with new osteoid. Mechanisms causing the osteoblastic functional deficiency are not fully understood. Evidence exists for impaired regulation of osteoblast function resulting from altered production of, or sensitivity to, systemic or local growth factors such as growth hormone and insulin-like growth factor 1 (IGF-1). ~2 Aging also brings a decrease in intestinal calcium absorption. The most potent regulator of intestinal calcium absorption is 1,25(OH)2D. Activity of the renal hydroxylase that converts 25(OH)D to 1,25(OH)zD falls with aging; the consequence is decreased production of physiologically active vitamin D. The combination of decreased formation of 1,25 (OH) zD and a relative insensitivity of the intestine to this active metabolite leads to the diminished intestinal calcium absorption. Additionally, many elderly persons have low dietary calcium intake. In the recent National Health and Nutrition Examination Survey (NHANES), one-third of the elderly women surveyed had dietary calcium intake of less than 400 mg daily, t3 Another cause of decreased bone density in the elderly is vitamin D deficiency severe enough to cause osteomalacia. Factors contributing to the vitamin D de-

Bone Loss of Menopause Estrogen deficiency causes accelerated bone loss. The bone loss is greatest for the first five to ten years of menopause, but some bone loss related to estrogen deficiency may occur until age 70. ]5 Estrogen has an inhibitory effect on bone resorption; the biophysiologic mechanisms of the inhibition are not well understood. When the inhibitory effect is lost there is a relative increase in osteoclast bone resorption, with the result being larger and more numerous resorption cavities. Normal osteoblast function is inadequate to fill these cavities. In response to the increased bone resorption, parathyroid hormone (PTH) secretion falls. The decline in serum PTH level leads to an impairment in renal hydroxylation of 25(OH)D and, consequently, a fall in the production of 1,25(OH)2 D. Lower levels of 1,25 (OH) zD decrease intestinal calcium absorption.

Involutional Osteoporosis Riggs and Melton have described two patterns of primary involutional osteoporosis (Table 2). Type I (postmenopausal) osteoporosis is characterized by accelerated bone loss due primarily to estrogen deficiency (Fig. 2). In the early postmenopausal period, the loss of 2 - 3% of bone mass per year is predominantly in trabecular bone, particularly the axial skeleton and the distal forearm. Type II (age-related) osteoporosis is characterized by bone loss due to diminished osteoblast function as well as decreased gut calcium absorption and secondary hyperparathyroidism (Fig. 3). Bone loss of 0 . 3 0.5% of bone mass per year begins at age 40, continues into late life, and affects men and women equally and trabecular and cortical bone equally.

TABLE 2 Patterns of involutional Osteoporosis* TypeZ

Type1 Age

5 0 - 75 years

> 70 years

Gender Type of bone loss

PredominantJywomen Trabecular

Men and women Trabecularand cortical

Rate of bone loss

2 - 3%/year in early menopause

0.3- 0.5%/year

Fracture sites

Vertebrae, distal radius

Vertebrae and hip

Parathyroid hormone level Calciumabsorption Causes

Decreased Decreased Estrogen deficiency

Increased Decreased Osteoblastdysfunction; fall in calciumabsorption

*Source: RiggsBL, Melton LJ 111.Medicalprogress series: involutional osteoporosis.N Engl J Med. 1986;314:1676.

JOURNAL OFGENERAL INTERNAL MEDICINE,Volume 7 (September/October), These two patterns of bone loss that occur universally in the population result in distinct fracture patterns, t~ In women, the accelerated postmenopausal loss of trabecular bone manifests epidemiologically as a sharp rise in the incidence of Colles' fractures and vertebral fractures five to ten years after menopause. In both men and women, the cortical and trabecular bone loss that is age-related, not gender-related, leads to a rise in hip fracture incidence later in life.

Decreasedestrogen I

I

Increasedboneresorption

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CLINICAL PRESENTATION AND EVALUATION The general internist is most frequently called upon to address several osteoporosis-related clinical issues: • Evaluation of the need for estrogen replacement therapy (ERT) in menopausal women • Evaluation and management of patients who present with osteoporotic fractures • Evaluation of an asymptomatic patient whose bones are found to be osteopenic on a routine radiograph • Prevention strategies for osteoporosis

Evaluation of the Need f o r

I Increasedserum calcium I

Decreased PTHsecretion 1

Decreasedreial production of 1,25(OH)D Decreasedcalciumabsorption I FIGURE Z. The pathophysiologic cascade of type i osteoporosis. Based on information obtained from Riggs and Melton."

ERT

at Menopause

When begun shortly after menopause, ERT delays the accelerated trabecular bone loss that occurs during the ensuing five to ten years. Long-term ERT reduces the risk of osteoporotic fractures by 50%. 17 There are other potential benefits of long-term E R T - - m a i n l y the improvement of lipid profile and decreased cardiovascular mortality rates. In the Lipid Research Clinics Program Follow-up Study, the ageadjusted relative risk of cardiovascular disease deaths in women using unopposed estrogens compared with nonusers was 0.3438 Oral estrogens decrease low-density lipoprotein (LDL) and increase high-density lipoprotein (HDL) levels. Unopposed estrogen provides the greatest benefit, but at usual doses progestins decrease this effect only slightly, tg' z0 Consideration of ERT should be given to all women

I Decreased1,25(OH)Dproduction ,1

I

Decreasedcalciumabsorption ]

IncreasedPTH secretion

,L

I

Increasedboneresorption I

FIGURE 3. The pathophysiologic cascadeof type II osteoporosis. Basedon information obtained from Riggs and Melton. '

I

I

Impairedosteoblastfunction I

y

Boneloss I

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Fleming, OSTEOPOROSlS

w h o are in early m e n o p a u s e . The decision for or against h o r m o n e therapy must b e individualized and r e a c h e d jointly b y the patient and physician after a careful rev i e w of the risks and benefits. If the patient has an absolute contraindication to estrogen therapy, t h e n no further consideration is given. If there is no contraindication, then a clinical assessment of osteoporosis risk follows. Factors such as race, dietary history, exercise habits, t h e r a p e u t i c drug use, and t o b a c c o and alcohol use provide some indication of risk. However, these clinically available data are of limited utility in identifying w o m e n w i t h low b o n e mass. 2~ There have b e e n recent analyses of the application of b o n e density m e a s u r e m e n t s in screening for osteoporosis. 22"24 The utility of the b o n e density m e a s u r e m e n t in the decision-making process is based on the strong relationship b e t w e e n b o n e density and s u b s e q u e n t fracture. A single accurate b o n e mass m e a s u r e m e n t at any site predicts s u b s e q u e n t fractures of all types. 2~ In a study of 5 21 w h i t e w o m e n , Hui et al. f o u n d that a single b o n e mass m e a s u r e m e n t of the radius was predictive of nonvertebral fractures at all sites, including the hip and forearm.26, z7 In a p r o s p e c t i v e study of 9 , 7 0 3 n o n b l a c k w o m e n aged 65 and older, C u m m i n g s et al. found that m e a s u r e m e n t s of density of a p p e n d i c u l a r b o n e using single-photon a b s o r p t i o m e t r y (SPA) p r e d i c t e d future hip fractures. After age adjustment, the relative risk of hip fractures was 1.55 (95% CI 1 . 1 3 - 2 . 1 1) for a decrease of 1 SD in b o n e density at the distal radius. 2s Using b o n e density measurements, fracture threshold has b e e n e m p i r i c a l l y p l a c e d at 1.0 g p e r c m 2 for the vertebrae and p r o x i m a l f e m u r and 0.4 g / c m 2 for the distal radius. 29 I f a p e r i m e n o p a u s a l w o m a n is in the u p p e r third of the age-related distribution of b o n e density, then her risk for fractures is l o w and she n e e d not receive ERT for osteoporosis prevention. If a w o m a n is in the middle third of the distribution, a reasonable m a n a g e m e n t a p p r o a c h is to repeat the density determination in several years and, if there has b e e n a significant loss during that time, to reconsider ERT. If the w o m a n is in the lower third of the distribution, t h e n ERT is r e c o m m e n d e d . Bone density determinations are readily available

to most clinicians; four t e c h n i q u e s are used. 3° Singlep h o t o n a b s o r p t i o m e t r y can be done in the office and measures the density of a p p e n d i c u l a r b o n e - c o m m o n l y the distal radius or the calcaneus. It is precise and relatively l o w in cost, and radiation and scan times are low. It does not measure axial b o n e density. Dual-photon a b s o r p t i o m e t r y measures density of the spine and the p r o x i m a l femur; a disadvantage is long scan time. Quantitative c o m p u t e d t o m o g r a p h y (QCT) is used primarily to measure the density of the spine but can be used at other skeletal sites as well. Radiation e x p o s u r e is higher with Q C T than with the o t h e r techniques, and QCT is generally the most costly. The stateof-the-art b o n e density m e a s u r e m e n t t e c h n i q u e is dualenergy x-ray a b s o r p t i o m e t r y (DEXA), w h i c h is fast and has a precision error of 1% or less, low radiation, and a cost that is c o m p a r a b l e to those of the other t e c h n i q u e s (Table 3).

Evaluation of Patients Presenting with Osteoporotic Features When the initial patient presentation of osteoporosis is an acute fracture, the physician's tasks are to manage the fracture appropriately, to d e t e r m i n e the cause of b o n e loss, to assess the severity of b o n e loss, and to plan treatment that will p r e v e n t further b o n e loss or even restore bone. The history should b e focused to d e t e r m i n e the dietary intake of calcium and vitamin D, to d e t e r m i n e w h e t h e r there have b e e n previous fractures, to detail the m e n o p a u s e history, and to d e t e r m i n e exercise habits, tobacco and alcohol use, and the use o f therapeutic agents (particularly thyroid r e p l a c e m e n t therapy or corticosteroid use). A detailed system r e v i e w serves to disclose clues to the existence of an underlying process causing osteoporosis, for e x a m p l e , hyperthyroidism or gastrointestinal disease. The physical e x a m i n a t i o n should include a careful m e a s u r e m e n t o f height, an examination of the spine for deformity or percussion tenderness, and an exploration for signs that w o u l d suggest an underlying cause of osteoporosis.

TABLE 3 Bone Density Measurement Techniques*

Accuracy error Precision error

Scan time Radiation Cost

SPAt

DPA:I:

OCT§

DEXA¶

4 - 5% 1-2% 1O- 20 mins 2 0 - 1O0 #Sv S35-120

3- 6% 2-4% 2 0 - 60 mins 50 pSv $1 O0

5 - 10% 3% 1O- 20 mins 1,000 #Sv $ 1 0 0 - 400

4% 1% 10 1O- 30 #Sv $120

*Based on information obtained from Riggs3 and Johnston et al.3° tSPA = single-photon absorptiometry. *DPA = dual-photon absorptiometry. §QCT = quantitative computed tomography. ¶DEXA = dual-energy x-ray absorptiometry.

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Baseline laboratory work is useful in helping to differentiate primary and secondary osteoporosis. A c o m p l e t e blood count, a chemistry profile, the erythrocyte sedimentation rate, urinalysis, and sensitive thyroid-stimulating h o r m o n e (TSH) should be obtained; in primary osteoporosis these test results are normal. Symptoms of weight loss, fatigue, or bone pain indicate the need for serum and protein electrophoresis. An anemia, an abnormal differential count, elevated calcium, low phosphorous, low TSH, and elevated alkaline phosphatase are indicators for further evaluation. Except w h e n fractures are healing, alkaline phosphatase levels are normal in involutional osteoporosis. An elevated alkaline phosphatase of bone origin is an indicator of increased bone turnover and, in the clinical setting of osteopenia, should cause the clinician to consider osteomalacia, hyperparathyroidism, Paget's disease, or skeletal metastases. In the elderly, if the alkaline phosphatase is elevated, measurement of the vitamin D level should be done to exclude osteomalacia. An initial record of vertebral deformities is provided by thoracic and lumbar spine radiographs, w h i c h are useful w h e n evaluating subsequent episodes of back pain. An initial measurement of bone density serves as a baseline w h e n following the progression of disease or the efficacy of therapeutic interventions.

Evaluation of Osteopenia Found on a Routine Radiograph Primary physicians c o m m o n l y receive radiograph reports with a diagnosis of spinal osteopenia or thoracic or lumbar vertebral abnormalities (compression, concavity, or anterior wedging). Because radiographs may have the appearance of osteopenia for technical reasons, the radiologist's diagnosis of osteopenia is not specific for osteoporosis. Likewise, the vertebral abnormalities are not specific for osteoporosis but may be due to trauma in the distant past or positioning. Before embarking on a costly evaluation of osteoporosis, a bone density measurement of the spine should be done to be certain that the apparent osteopenia is due to osteoporosis. If osteoporosis is diagnosed by bone density measurement, then the clinical evaluation should be carried out and management planned.

Prevention Strategies for Osteoporosis Primary physicians should be educators in the prevention of osteoporosis. Osteoporosis prevention is a lifelong process that begins in childhood and adolescence with sound dietary habits that ensure adequate calcium and vitamin D intake. Prevention includes the health-related habits of nonsmoking, restrained alcohol use, and regular exercise. These measures help to max-

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imize peak bone density and make it less likely that the universal bone loss that occurs later in life will decrease the bone density to a level that is b e l o w fracture threshold. Prevention in adulthood includes ERT for w o m e n at risk and adequate calcium intake, exercise, alcohol moderation, and tobacco abstinence for both men and women.

PHARMACOLOGIC PREVENTION AND TREATMENT OF OSTEOPOROSIS The use of pharmacologic agents in osteoporosis prevention and treatment is either antiresorptive (slowing the rate of bone loss) or formation-stimulating (restoring lost bone). Antiresponsive therapies include estrogen replacement, calcitonin, and calcium supplementation. These therapies slow the rate of bone loss, and after a period of several months a new steady state exists with balanced bone resorption and formation. The antiresorptive therapies are c o m m o n l y used as prevention in postmenopausal w o m e n and in patients with asymptomatic osteoporosis, or are initiated after a first osteoporotic fracture. Formation-stimulating therapies include 1) fluoride and 2) coherence, or activate, depress, free, and repeat (ADFR), regimens. These agents stimulate bone formation more than bone resorption, with the therapeutic goal of increasing bone density to a level that is above fracture threshold. Formation-stimulating therapies are most useful in patients w h o have e x p e r i e n c e d repeated painful and debilitating fractures. Currently, we await clinically acceptable formation-stimulating therapies. Fluoride stimulates the formation of qualitatively deficient trabecular bone and has been shown to increase fracture rates in cortical bone. 3~ The coherence therapies appear promising but general use awaits more evaluation. Estrogen and calcitonin are the only agents approved by the Food and Drug Administration (FDA) for osteoporosis therapy.

Calcium Supplementation Calcium supplementation alone does not appear to slow the accelerated early postmenopausal bone loss that occurs primarily in trabecular bone. In a prospective two-year study, Riis et al. did serial measurements of bone density in the forearm, the entire body, and the spine in w o m e n assigned to one of three treatment groups: 1) percutaneous estrogen, 2) 2,000 m g / d a y oral calcium, and 3) placebo. They found that calcium supplementation was not as effective as estrogen therapy in preventing the early postmenopausal trabecular bone loss. 32 Ettinger et al. have shown that calcium supplementation in early postmenopause lowers the m i n i m u m dose of estrogen n e e d e d to prevent bone loss to 0.3 mg conjugated estrogen per day. 33

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Dawson-Hughes et al. reported a double-blind, placebo-controlled, randomized trial that evaluated the effect of calcium on bone loss from the spine, femoral neck, and radius in 301 healthy postmenopausal women, half of whom had a calcium intake of less than 400 mg/day and the other half an intake of 4 0 0 - 6 5 0 mg/day. In women who were early menopausal, (menopause five or fewer years earlier), bone loss from the spine was rapid and was not affected by supplementation with calcium. In the older postmenopausal women, who had daily calcium intake of less than 400 mg, bone loss could be reduced by increasing daily calcium intake to 800 mg. 3~ Beginning in midlife, adequate daily calcium intake for both men and women is 1 , 2 0 0 - 1 , 5 0 0 mg. If dietary intake is less than this amount, then supplementation should be given. Nonprescription preparations such as calcium carbonate (40% elemental calcium) and calcium gluconate (9% elemental calcium) are most often used. Absorption of calcium from calcium carbonate requires the presence of gastric acid; in those elderly patients with achlorhydria, it is poorly absorbed. In the elderly who have a diet containing less than 400 mg of calcium, the clinician must keep in mind the possibility of concomitant vitamin D deftciency and consider supplementation. This is especially likely for the housebound elderly in northern latitudes. In review, calcium supplementation has little or no preventive effect on the rapid, accelerated early postmenopausal bone loss due to estrogen deficiency. Calcium supplementation decreases the slower bone loss of type II osteoporosis in individuals whose usual diets contain less than 400 mg of calcium.

Estrogen Replacement Therapy Estrogen replacement therapy effectively prevents the accelerated trabecular bone loss that occurs in the first five years after menopause. 3s Genant et al. used QCT to measure vertebral bone density and SPA to measure peripheral bone density in women who were followed for two years after natural menopause or oophorectomy. The oophorectomized women who took placebo or less than 0.6 mg of conjugated estrogen daily had bone loss of 16 - 19% from the spine and 1 - 3% from peripheral sites. Women who took 0.6 mg daily had no significant bone loss during the two-year period. 36 Ettinger et al. used a retrospective cohort method to study the effect of long-term ERT on bone loss and fracture rates. They found a fracture rate that was 53.7% lower in the estrogen group than in case-matched controls. The relative risk of osteoporotic fracture was 2.2 for controls as compared with estrogen users. 17 Estrogen replacement therapy prevents the accelerated trabecular bone loss for as long as continued.

When hormone therapy is stopped, bone loss resumes. Most authorities recommend that ERT be continued for 10 - 15 years. Even though bone loss resumes after therapy is stopped, the therapy period delays the onset of loss so that most women will not develop symptomatic osteoporosis in their remaining years. Estrogen replacement therapy is beneficial if started within five years of menopause; benefits of starting estrogens later than five years after menopause are not clear. The only generally accepted contraindications to ERT are a personal history of breast cancer and a history of a deep venous thrombosis with no clear precipitating factor such as trauma or surgery. Preferred ERT regimens are continuous estrogen therapy with cyclic progestin or continuous combined therapy with daily estrogen and daily progestin. 37 Women who have had hysterectomies are given daily estrogen; no progestin is necessary. When using the continuous estrogen with cyclic progestin method, a daily dose of estrogen (0.625 mg Conjugated estrogen) is given, and progestin as 10 mg medroxyprogesterone acetate is given on days 1 to 14 of the calendar month. Withdrawal bleeding occurs within a day or two after the progestin is stopped. When using the continuous combined therapy, a daily dose of estrogen (0.625 mg conjugated estrogen) is given and a daily dose of progestin as 2.5 mg medroxyprogesterone acetate is given. This regimen is intended to give an inactive and stable endometrium with no withdrawal bleeding. The estrogen component of these replacement regimens may be administered as transdermal patches (0.05 mg estradiol transdermal system) applied twice weekly. Absorption through the skin results in a therapeutic serum level of estradiol with lower circulating levels of estrone and estrone conjugates than when the estrogen is given orally and there is initial hepatic metabolism. The long-term risks of ERT are still unclear. Taking progestins, either cyclically or daily, eliminates the risk of endometrial cancer associated with unopposed estrogens. The relationship between ERT and the development of breast cancer remains controversial. 38' 39

Calcltonln Postmenopausal osteoporosis is due to bone resorption in excess of bone formation. Calcitonin is a potent inhibitor of osteoclastic bone resorption. Since no evidence exists that a deficiency of calcitonin is causative in osteoporosis, calcitonin therapy should be considered a pharmacologic antiresorptive therapy, not a replacement therapy. Existing evidence shows that daily or alternate-day injections of salmon calcitonin in combination with oral calcium may reduce bone resorption and increase bone density in women with postmenopausal osteoporosis. The bone gain is

JOURNALOFGENERALINTERNALMEDICINE. Volume 7 (September/October), 1992

small and in many patients starts to reverse within 12 20 months, despite continued t h e r a p y ) ° Because of its difficulty in administration, its expense, and lack of evidence that it reduces fracture rates, calcitonin therapy should be considered only as an alternative to ERT when antiresorptive therapy is needed and there is a contraindication to estrogen use.

Fluoride Therapy Sodium fluoride stimulates bone formation. Although not approved by the FDA for the treatment of osteoporosis, it has been widely used for that purpose in patients with symptomatic disease. The attractiveness of fluoride therapy is that it stimulates new bone growth in contrast to the antiresorptive therapies calcium and estrogen. Riggs et al. performed a four-year, prospective, randomized, double-blind, placebo-controlled trial of sodium fluoride in women with type I osteoporosis and compression fractures. 31 The participants were randomized to receive either sodium fluoride (75 mg/ day) or placebo. Compared with the placebo group, the treatment group showed a 3 5% increase in lumbar spine density, a 12% increase in femoral neck density, and a 10% increase in femoral trochanter density. Density decreased by 4% in the radial shaft in the treatment group. The number of new vertebral fractures was the same for the study groups, but the number of nonvertebral fractures was higher in the fluoride group (p < 0.01). Side effects with fluoride therapy were c o m m o n - - m o s t often nausea or bloating and lower extremity pain. Riggs concluded that therapy with fluoride increases trabecular bone density but decreases cortical bone density; it did not change vertebral fracture rates but did increase nonvertebral fractures. At present there is no support for the efficacy of fluoride therapy in the management of osteoporosis. 41

Cyclical Etidronate Therapy When phagocytosed by osteoclasts, organic bisphosphonates inhibit cellular metabolic activity and decrease osteoclastic bone resorption. The bisphosphonate etidronate has been used in clinical trials of osteoporosis in protocols known as coherence therapy or ADFR.42 It is hypothesized that repeated cycles of stimulation and depression of osteoblast activity will cause a synchronization of bone resorption and formation. Osteoclasts are activated with oral phosphates, then depressed by the administration of a diphosphonate (etidronate). Osteoblasts form new bone at sites where there was prior bone remodeling initiated by the osteoclast activation. The cycle is repeated. Two recent double-blind, prospective trials of the treatment for postmenopausal osteoporosis with intermittent oral etidronate have been reported. Storm and

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collaborators43 used oral etidronate or placebo for two weeks, followed by 13 weeks of no drug. The sequence was repeated ten times for a total of 150 weeks. Both groups were given oral supplements of calcium and vitamin D daily. Vertebral density increased significantly after 150 weeks in the etidronate group, but decreased in the placebo group. After 60 weeks, the etidronate group had significantly fewer new vertebral fractures than did the placebo group. Watts et a1.,44 in a multicenter study, found that intermittent cyclical etidronate therapy increased spine density and reduced the rate of new vertebral fractures in women with postmenopausal osteoporosis. These innovative therapies provide some optimism for managing patients with repeated osteoporotic features.45 More investigation is needed before etidronate or other bisphosphonates are approved for routine clinical use.

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