Osteoporosis has been defined as a systemic skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength is determined by many factors, including bone mass. Bone mass is estimated in clinical practice by the measurement of area bone mineral density (BMD), the quantity of mineral (grams of calcium) divided by the area of the bone, using the technique of dual x-ray absorptiometry (DXA). There is a strong nonlinear relationship between BMD and the risk of fracture, such that for every decrease in one standard deviation below the age-adjusted mean for total hip BMD, the risk of hip fracture increases by a factor of greater than two. The World Health Organization (WHO) defined osteoporosis in white women as a BMD measured at the femoral neck of 2.5 or more standard deviations below the mean of young white women aged 20 to 39 years. This definition has been generalized to nonwhite women and men, with the recommendation that normative data for young persons should be sex specific.
The most important osteoporotic fractures, from the standpoint of both incidence and consequences, are vertebral and hip fractures. Systematic reviews and meta-analyses of placebo-controlled randomized clinical trials (RCTs) have demonstrated that treatment of postmenopausal women with either prevalent vertebral fractures or low BMD (femoral neck or total hip BMD T-score of −2.0 or below) can reduce the risk of vertebral and nonvertebral, including hip fractures. Similarly, treatment of men with low BMD and adults receiving chronic oral glucocorticoid therapy has been shown to increase BMD and reduce the risk of vertebral fractures.
This chapter reviews recommendations for identifying persons who should undergo measurement of BMD, persons with low BMD who should receive treatment to reduce their risk of fracture, and the therapies available in the United States for those individuals. Drugs not approved for treatment of osteoporosis in the United States, such as strontium ranelate, human parathyroid hormone 1-84, and tibolone are not discussed. Furthermore, surgical management of fractures, including the use of kyphoplasty and vertebroplasty for management of back pain due to vertebral fractures, are not covered; the reader is referred to a recent chapter on this topic.
WHO SHOULD HAVE BMD MEASURED?
The most widely recognized guidelines in the United States are those of the National Osteoporosis Foundation (NOF) that were updated in 2008 ( Table 24-1 ). The NOF currently recommends that all postmenopausal women and men age 50 and older should be evaluated for osteoporosis risk in order to determine the need for BMD testing. The NOF recommends that BMD be measured using DXA in (1) all postmenopausal women aged 65 and older and men age 70 and older, regardless of risk factors; (2) younger postmenopausal women and men age 50 to 69 about whom there is concern based on their risk factor profile; (3) women in the menopausal transition if there is a specific risk factor associated with increased fracture risk such as low body weight, prior low-trauma fracture or use of high-risk medications; (4) adults who have a fracture after age 50; (5) adults with a condition ( Table 24-2 ) or taking a medication ( Table 24-3 ) associated with low bone mass or bone loss; (6) anyone being considered for pharmacologic therapy for osteoporosis; (7) anyone being treated for osteoporosis, to monitor treatment effect; and (8) anyone not receiving therapy in whom evidence of bone loss would lead to treatment.
| Women age 65 and older, and men age 70 and older, regardless of clinical risk factors |
| Younger postmenopausal women and men age 50 to 69 years with risk factors for fracture |
| Women in the menopausal transition with risk factors for fracture, such as low body weight, prior low-trauma fracture, or use of high-risk medication |
| Adults who have a low-trauma fracture after age 50 |
| Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for three months or longer) associated with low bone mass or bone loss |
| Anyone being considered for pharmacologic therapy for osteoporosis |
| Anyone being treated for osteoporosis, to monitor treatment effect |
| Anyone not receiving therapy in whom evidence of bone loss would lead to treatment |
| Genetic Disorders |
| Cystic fibrosis |
| Homocystinuria |
| Osteogenesis imperfecta |
| Ehlers-Danlos syndrome |
| Hypophosphatasia |
| Glycogen storage disease |
| Gaucher’s disease |
| Porphyria |
| Idiopathic hypercalciuria |
| Hemochromatosis |
| Marfan’s syndrome |
| Riley-Day syndrome |
| Menkes’ steely hair syndrome |
| Hypogonadal States |
| Anorexia nervosa |
| Hyperprolactinemia |
| Turner’s syndrome |
| Panhypopituitarism |
| Athletic amenorrhea |
| Klinefelter’s syndrome |
| Ovarian failure |
| Androgen insensitivity |
| Endocrine Disorders |
| Acromegaly |
| Cushing’s syndrome |
| Adrenal insufficiency |
| Thyrotoxicosis |
| Hyperparathyroidism |
| Diabetes mellitus, type I |
| Gastrointestinal Diseases |
| Gastrectomy |
| Malabsorption |
| Primary biliary cirrhosis |
| Celiac disease |
| Inflammatory bowel disease |
| Hematologic Disorders |
| Hemophilia |
| Multiple myeloma |
| Systemic mastocytosis |
| Thalassemia |
| Sickle cell disease |
| Leukemias and lymphomas |
| Rheumatic Diseases |
| Ankylosing spondylitis |
| Lupus |
| Rheumatoid arthritis |
| Miscellaneous |
| Alcoholism |
| Emphysema |
| Multiple sclerosis |
| Amyloidosis |
| Epilepsy |
| End-stage renal disease |
| Depression |
| Scoliosis |
| Post-transplant bone disease |
| Immobilization |
| Sarcoidosis |
| Muscular dystrophy |
| Metabolic acidosis |
| Heart failure |
| Anticoagulants |
| Anticonvulsants |
| Antidepressants |
| Aromatase inhibitors |
| Cancer chemotherapeutic drugs |
| Cyclosporine A and tacrolimus |
| Depo-medroxyprogesterone |
| Glucocorticoids |
| Gonadotropin-releasing hormone agonists |
| Lithium |
| Proton-pump inhibitors |
| Thyroxine |
The evidence that links universal testing of women aged 65 and older with a reduced rate of fractures is derived from two studies. LaCroix and colleagues randomized more than 9000 women aged 60 to 80 years who were not taking hormone therapy or other osteoporosis medications to one of three groups: universal testing (n = 1986), testing based on results of the SCORE questionnaire (n = 1940), and testing based on results of a 17-item questionnaire adapted from known risk factors for hip fracture (n = 5342). During a mean follow-up of 33 months, the rate of osteoporotic fractures was 74.11, 99.44, and 91.77 per 1000 woman-years, respectively ( P < 0.05 comparing the universal screening group with the other two groups). The rate of hip fractures was also lower in the universal screening group, but differences were not statistically significant (8.54, 9.04, and 13.31 per 1000 woman-years, respectively). These results were supported by an analysis of data from the Cardiovascular Health Study. In this observational cohort study, 1378 participants enrolled in the Sacramento County (California) and Allegheny County (Pennsylvania) sites completed measurement of BMD at the hip, whereas 1685 participants enrolled in the Washington County (Maryland) and Forsyth County (North Carolina) sites received usual care; the mean age of participants was 76 years, the majority were women and more than 80% were white. The incidence of hip fractures over a mean follow-up of 4.9 years was 4.8 and 8.2 per 1000 person-years in the screened group and usual care group, respectively: adjusted relative risk (RR) = 0.64 (95% confidence interval [CI], 0.41–0.99). There was no evidence of a statistical interaction between screening and sex, age group or race; however, there were only four hip fractures in the 532 black participants. Hence, these two studies support the recommendations for universal BMD testing in older women.
WHO SHOULD BE TREATED TO REDUCE FRACTURE RISK?
Solomon and colleagues performed a systematic review of the English-language literature using MEDLINE and HealthStar for the period between January 1992 and December 2003 to identify osteoporosis treatment guidelines. They identified 18 unique guidelines; 17 provided recommendations for postmenopausal women, and 13 provided recommendations for men. There was considerable heterogeneity in the recommendations, however.
Delmas and colleagues, in outlining the position of the International Osteoporosis Foundation (IOF), concluded that treatment of postmenopausal women with established osteoporosis is always cost effective and that additional scenarios exist when treatment is cost effective. These additional scenarios depend upon crossing an “intervention threshold,” where the future morbidity from osteoporotic fractures, largely derived from the risk and costs of hip fracture, exceeds the costs of interventions that have been shown to reduce the risk of these fractures. Additional risk factors that contribute to the estimate of this risk, independent of BMD, were identified through a series of meta-analyses conducted by Professor John Kanis and colleagues under the auspices of the WHO; these risk factors include age, sex, prior history of fragility fracture, parental history of hip fracture, current smoking, use of systemic glucocorticoids, alcohol intake in excess of 3 units per day, and presence of rheumatoid arthritis ( Table 24-4 ). An algorithm named the WHO Fracture Risk Assessment Tool (FRAX) was developed to allow calculation of the person-specific 10-year risk for both a major osteoporotic fracture (hip, shoulder, wrist and clinical vertebral combined) and a hip fracture alone ; FRAX can be accessed at www.shef.ac.uk/FRAX/index.htm ( Fig. 24-1 ). If BMD has not been measured, the person’s weight and height can be substituted in the calculation. Some caveats need to be recognized by providers who are going to use FRAX in their practices: (1) it is not intended for use in persons younger than 50 years of age; (2) it applies only to previously untreated patients; (3) lumbar spine BMD cannot be substituted for either femoral neck or total hip BMD (hence, it cannot be used in persons with bilateral total hip arthroplasties); and (4) before entry into the computer algorithm, the patient’s BMD T-score must be converted to an appropriate T-score using the “FRAX Patch,” which is available on the NOF’s website (“ www.nof.org/frax_patch.htm ”).
| Current age |
| Sex |
| Weight |
| Height |
| History of previous spontaneous or low-trauma fracture, including radiographic vertebral fracture without symptoms |
| Parental history of hip fracture |
| Current smoking |
| Use of glucocorticoids for more than 3 months at a dose of prednisolone of 5 mg daily or more (or equivalent doses of other glucocorticoids) |
| Alcohol intake of 3 or more units per day |
| Rheumatoid arthritis |
| Other causes of secondary osteoporosis |
The NOF suggests, based on cost-effectiveness modeling, that postmenopausal women and men age 50 and older should be considered for treatment if (1) they have either a hip or vertebral fracture; (2) they have osteoporosis based on a BMD T-score of −2.5 or below at the femoral neck or lumbar spine; or (3) they have low BMD (T-score between −1.0 and −2.5 at the femoral neck or lumbar spine) with a 10-year risk of a hip or a major osteoporotic fracture of 3% or 20% or greater, respectively ( Table 24-5 ). Note that glucocorticoid use is included among the factors considered in estimating the 10-year fracture risk; hence, the FRAX model is applicable to patients being considered for treatment of glucocorticoid-induced osteoporosis. An algorithm developed by the author summarizing the approach to BMD testing and the use of BMD in making decisions about whom to treat based on the NOF recommendations is shown in Figure 24-2 .
| A vertebral or hip fracture |
| Bone mineral density T-score of −2.5 or below at the femoral neck or lumbar spine |
| Low bone mass and a 10-year probability of major osteoporotic fracture of 20% or higher |
| Low bone mass and a 10-year probability of hip fracture of 3% or higher |
TREATMENT TO REDUCE FRACTURE RISK
The management of the individual patient with osteoporosis requires a combination of nonpharmacologic and pharmacologic modalities. Before instituting pharmacologic therapies, however, all patients should be evaluated for secondary causes of osteoporosis and, if identified, these conditions should be treated appropriately. A set of routine laboratory tests that are useful to identify common causes of secondary osteoporosis includes a complete blood count and differential, erythrocyte sedimentation rate, routine chemistry profile, 25-hydroxyvitamin vitamin D level (see later), thyroid-stimulating hormone, if the patient is receiving thyroid hormone supplementation and a 24-hour urine for measurement of calcium excretion; other tests can be ordered if any of the above are abnormal ( Table 24-6 ). In addition, serum testosterone levels should be measured in all men.
| Routine |
| Complete blood count |
| Erythrocyte sedimentation rate |
| Comprehensive metabolic profile |
| 25-hydroxyvitamin D level |
| Thyroid stimulating hormone, if patient on thyroid replacement |
| Serum testosterone level (in men only) |
| 24-hour urine collection for calcium excretion |
| Optional |
| Serum parathyroid hormone (PTH) |
| Serum and urine protein electrophoresis |
| Biochemical markers of bone turnover |
Nonpharmacologic Modalities
Key components of the nonpharmacologic treatment program are patient education, adequate nutrition, particularly protein, calcium and vitamin D intake, muscle strengthening and balance exercises to prevent falls, smoking cessation, and avoidance or limitation of alcohol intake.
Patient Education
Several studies have demonstrated an association between adherence and persistence with oral bisphosphonates and fracture risk reduction ; hence, use of educational materials coupled with appropriate follow-up and reinforcement directed toward increasing both adherence and persistence with osteoporosis medications should be part of the management strategy for every patient.
Calcium Intake
All patients should achieve a daily intake of dietary calcium of at least 1200 mg, including supplements. Dietary calcium intake can be estimated by multiplying the number of 8-ounce servings of milk and 6-ounce servings of yogurt by 300 mg and the number of 1-ounce servings of cheese by 200 mg and adding this number to 250 mg for the nondairy sources of calcium. Calcium supplements should be taken if this total does not equal or exceed 1200 mg. Calcium supplements most commonly come either as calcium carbonate or calcium citrate. Calcium carbonate should be taken with meals because of better absorption in an acid milieu; calcium citrate can be taken either with or between meals. If the amount of supplements required is greater than 500 mg per day, then the dosage should be divided. Although calcium supplementation has been shown to have a small positive effect on bone mineral density, it has not been shown to have a significant effect on fracture risk reduction.
Fall Prevention
Both the type of fall and the biomechanics of the fall are related to fracture risk in older women. Numerous risk factors for falls have been identified ( Table 24-7 ). Because of the multitude of risk factors for falls, a multifactorial approach to fall prevention has been advocated. This approach includes an assessment of the patient by an occupational or physical therapist with instructions in lifestyle modifications and muscle strengthening and balance exercise programs, as well as an assessment of medical conditions and medication use by a nurse or physician with modification of the treatment regimen to eliminate drugs associated with falling. Although this approach has been tested in RCTs and shown to reduce the incidence of falls in elderly individuals, it has not been shown to reduce the incidence of fractures.
|
Vitamin D
Sufficiency of vitamin D should be determined in all patients who are being considered for treatment for osteoporosis. Vitamin D status is best assessed by measurement of serum levels of 25-hydroxyvitamin D (25[OH]D) using either the DiaSorin radioimmunoassay (Stillwater, MN) or the gold standard technique of liquid chromatography–mass spectroscopy. A serum 25(OH)D level of 30 ng/mL (75 nmol/L) is considered the minimum of the normal or sufficient range. Patients with 25(OH)D levels below 20 ng/mL (50 nmol/L) are considered vitamin D deficient and should have their vitamin D stores corrected before beginning pharmacologic therapy for osteoporosis, particularly if they are going to be treated with a nitrogen-containing bisphosphonate. Several preparations and protocols are available for vitamin D repletion in these patients; the most common is using either vitamin D 2 (ergocalciferol) or D 3 (cholecalciferol) in doses of 50,000 units orally once weekly for 6 to 8 weeks. An alternative regimen that has been shown to be efficacious and safe in older nursing home residents is the use of ergocalciferol at a dose of 50,000 units three times a week for 4 weeks. Once her vitamin D stores are repleted, the patient should receive 800 to 1000 units of vitamin D 3 (cholecalciferol) orally once daily. Patients whose 25(OH)D levels are between 20 and 30 ng/mL (50 and 75 nmol/L) should receive 2000 units of vitamin D3 orally daily, with the dose reduced to 1000 units of vitamin D 3 once their 25(OH)D level reaches the normal range. Patients with malabsorption syndromes may require higher daily doses to maintain their serum 25(OH)D levels within the normal range. Vitamin D supplementation has been shown to be associated with a reduced incidence of falls and fractures. Indeed, there is evidence that the benefits of vitamin D supplementation are greatest when combined with calcium supplementation.
Pharmacologic Modalities
The approach to the choice of a pharmacologic regimen for the individual patient with osteoporosis or increased fracture risk, and to a lesser extent glucocorticoid-induced osteoporosis, is complex because one must consider not only the patient’s characteristics but also the benefits and risks of each of the individual drugs. This choice should be based, to the greatest extent possible, on the principles of evidence-based medicine wherein the evidence for efficacy and safety of each drug is derived from systematic reviews of RCTs with meta-analyses providing summary estimates for efficacy as measured by fracture risk reduction for vertebral and nonvertebral, including hip fractures, and tolerability as measured by rates of discontinuation for adverse events. MacLean and colleagues performed a systematic review in 2007 to describe the benefits in terms of fracture risk reduction and the harms from adverse events among and within the various classes of pharmacologic therapies for osteoporosis. They included a total of 76 RCTs and 24 meta-analyses in their efficacy analysis and 493 articles in their analyses of adverse events. They reported that, in high-risk groups, there was good evidence that alendronate, calcitonin, estrogen, ibandronate, risedronate, raloxifene, teriparatide and zoledronic acid reduced the risk of vertebral fractures, and that alendronate, estrogen, risedronate, teriparatide, and zoledronic acid reduced the risk of nonvertebral fractures. The following sections will review data for agents approved by the US Food and Drug Administration for the treatment of osteoporosis, including nitrogen-containing bisphosphonates, calcitonin, estrogen, raloxifene, and teriparatide ( Table 24-8 ).
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