ch17
Content
C H A P T E R zzzzzzzzzzzzzzzzzzzzzzzzzzz
17
Osteoporotic Fragility Fractures Osteoporotic Fragility Fractures
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Joseph M. Lane, M.D. Charles N. Cornell, M.D. Margaret Lobo, M.D. David Kwon, M.S.
EPIDEMIOLOGY
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is the most prevalent metabolic bone disease, affecting a large portion of the aging, predominantly female, population in the United States.108 On the basis of World Health Organization criteria, it is estimated that 15% of postmenopausal white women in the United States and 35% of women older than 65 years of age have frank osteoporosis.110 As many as 50% of women have some degree of low bone density in the hip. An estimated 1.2 million fractures annually are attributable to osteoporosis, including 538,000 vertebral, 227,000 hip, and 172,000 distal forearm (Colles’) fractures.54, 76, 94 Increasing age is significantly correlated with the incidence of fractures.77 Fractures in the wrist rise in the sixth decade, vertebral fractures in the seventh decade, and hip fractures in the eighth decade.107 One of every two white women experiences an osteoporotic fracture at some point in life.66 Among those who live to the age of 90 years, 32% of women and 17% of men sustain a hip fracture.75 Twenty-four percent of patients with hip fracture die within 1 year as a result; 50% require long-term nursing care, and only 30% ever regain their prefracture ambulatory status.18, 75, 78, 82 Of patients in nursing homes, 70% do not survive 1 year.3, 43, 44, 56, 60 The financial burden of osteoporosis is rapidly escalating as the population ages. Patients with fragility fractures create a significant economic burden. Treating osteoporosis is more costly than 400,000 hospital admissions and 2.5 million physician visits per year.109 Health care expenditures attributable to osteoporotic fractures were estimated as $13.8 billion, of which $10.3 billion was for the treatment of white women.90 The cost of acute and long-term care for osteoporotic fractures of the proximal femur alone has been estimated to exceed $10 billion annually in the United States.84 It is estimated that hip
fractures alone may cost the United States $240 billion in the next 50 years.107 These statistics indicate the need for increased physician awareness and diagnosis and, more important, emphasis on prevention of osteoporosis.
BONE AS A METABOLIC ORGAN
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The relation between metabolic bone disease and fracture healing depends on the role of the skeleton as a metabolic resource.62 Bone consists of a mineral fraction, hydroxyapatite crystals, and an organic fraction, largely (90%) type I collagen.79 The mineral fraction of bone makes up more than 98% of the body calcium.64 The bone, therefore, is the principal calcium reservoir of the body, and its specific architecture provides both structural support and an extensive bone surface for easy calcium mobilization. Bone is characterized as a composite material in which the collagen provides the tensile strength and hydroxyapatite the compressive strength.55 Bone is constantly renewing itself through a process of formation that is under cellular control.38 It is a dynamic connective tissue, and its responsiveness to mechanical forces and metabolic regulatory signals that accommodate requirements for maintaining the organ and connective tissue functions of bone are operative throughout life.68 The half-life of bone varies according to structural and metabolic demands. Bone formation is provided by osteoblast activity (measured by alkaline phosphatase and osteocalcin), and bone resorption is under osteoclast control (measured by N-telopeptides).79 The remodeling process and bone turnover appear to be coupled to and influenced by local humoral factors, biophysical considerations (Wolff’s law: ‘‘form follows function’’), and systemic demands.79 Vitamin D, parathy427
Copyright © 2003 Elsevier Science (USA). All rights reserved.
428
SECTION I • General Principles
roid hormone (PTH), and estrogen are among the hormones that control bone metabolism. Vitamin D, more specifically 1,25-dihydroxyvitamin D, is responsible for facilitating calcium absorption and osteoclastic resorption.41 Administration of PTH leads to the release of calcium from bone,53 and bone mass is directly related to the levels of estrogen in both men and women.98 Bone is primarily cortical (with a large volume and low surface area) or trabecular (with a large surface area and low volume). Because bone is resorbed and formed on surfaces, mainly the endosteal surface, trabecular bone, with its greater surface-to-volume ratio, is metabolically more active.50, 51, 61 The material properties of bone are, in large part, related to the microdensity of the material.9 Because the modulus of bone decreases only minimally with age, its primary strength is determined by its mass and structure.9, 52 The importance of structural distribution is evidenced by the greater bending and torsional strength of a tube compared with a rod of equal cross-sectional material area. Maximization of the moment of inertia (distribution of the mass away from the epicenter) in nature enhances the structural strength of bone, particularly when the mass is deficient. A 10% shift of bone outward can compensate for a 30% loss in bending and torque. In the aging human, loss of cortical bone mass is partially compensated by expansion of the diameter of the cortex. However, the increase in the diameter of long bones rarely exceeds 2% of the original diameter per year.30, 92 Therefore, the actual loss of cortical mass places elderly persons at an increasing risk of fracture. The structural strength is also related to connectivity—the degree of interconnection within bone.14, 91
MECHANISM OF OSTEOPENIC FRACTURE
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The composite structure of bone allows it to withstand compressive and tensile stresses as well as bending and torsional moments.97 Trabecular bone is often subjected to large impact stresses, whereas cortical bones often handle torque and bending. The vertebral body is largely protected by its trabecular bone, whereas the femoral neck depends on a mixture of cortical and trabecular bone for protection.9, 61 The hallmark of osteoporosis is deficient bone density and lack of connectivity.37, 73 The decreased bone mass associated with osteoporosis reduces the load-bearing ability of both cortical and trabecular bone, resulting in an increased risk of fracture. Areas of the skeleton rich in trabecular bone sustain the first consequences of osteoporosis; the trabecular bone is thinner in dimension and shows evidence of osteoclastic resorption, leading to disconnectivity of the trabecular elements.66 Trabecular bone is resorbed at a higher rate (8% per year) than cortical bone (0.5% per year) after menopause. Riggs and Melton93 recognized this discrepancy and developed the concept of two forms of osteoporosis with separate fracture patterns. Type I postmenopausal osteoporosis primarily affects women 55 to 65 years of age, is related to estrogen deficiency, results principally in trabecular bone loss, and is
manifest in spinal fractures. Type II senile osteoporosis affects both men and women (1:2 ratio) 65 years of age or older, is related to chronic calcium loss throughout life, results in cortical bone loss, and induces long bone fractures. Although bone mass is clearly related to fracture risk, a true fracture threshold can only be implied. Structure, fall tendency and type, ability of microfractures to heal before they become macrofractures, quality of bone, and such ill-defined factors as aging all play a role in fracture risk.1 The overlap of mass determination precludes clearly defining persons at absolute risk. Even at the lowest bone mass measurements, a percentage of individuals are free of fracture (Tables 17–1 and 17–2). For patients with hip fractures, Riggs and Melton93 demonstrated a fourfold increase in fracture rate with a 50% decrease in bone mass. The exponential increase in fracture rate with loss of bone mass is in agreement with the laboratory structural data of Carter and Hayes.9 Bone loss places the aging individual at greater risk of fracture, and fracture treatment therefore should include a bone maintenance strategy (see later discussion). Greenspan and co-workers36 documented etiologic factors for hip fractures in addition to bone density, including falls to the side, lower body mass index, and a higher potential to fall.39 Courtney and colleagues16 showed that the femur of an elderly person has half the strength and half the energy absorption capacity of the femur of a younger person. Falls from standing height exceed femoral breaking strength by 50% in elderly people but are below femoral fracture strength by 20% in the young. Cummings and associates19 included as hip fracture risks, in addition to low bone mass, aging, history of maternal hip fracture, tallness, lack of weight gain with aging, poor health, previously treated hypothyroidism, use of benzodiazepines, use of anticonvulsant drugs, lack of walking for exercise, lack of unsupported standing for 4 hours a day, a resting pulse rate higher than 80 beats per minute, and a history of any fracture after the age of 50 years. If two of these factors are present, 1 in 1000 individuals sustain a hip fracture in a given year. If five or more hip fracture risk factors are present in a patient who also has a low bone mass, the risk rises to 27 in 1000 individuals per year.20
FRACTURE HEALING AND OSTEOPOROSIS
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Normal fracture healing is a specialized process in which structural integrity is restored through the regeneration of
TABLE 17–1
DXA Values in Patients Undergoing Natural Menopause (P = .001)
Spinal fractures (n = 81) No spinal fractures (n = 225)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
0.80 (0.14 g/cm2) 0.89 (0.16 g/cm2)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abbreviation: DXA, dual-energy x-ray absorptiometry.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures TABLE 17–2
429
Spinal Fracture Prevalence in Postmenopausal Women as Related to DXA
DXA (g/cm2) 0.8–0.9 0.7–0.8 0.6–0.7 0.5–0.6 % With Spinal Fractures 26 33 51 63
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abbreviation: DXA, dual-energy x-ray absorptiometry.
bone.48 Fracture healing traditionally proceeds through the six stages of endochondral bone formation: impact, induction, inflammation, soft tissue callus (chondroid), hard tissue callus (osteoblastic), and remodeling.62 Although the stages from fracture through chondrogenesis are unaltered, the final two stages, hard callus and remodeling, are clearly susceptible to alteration in osteoporotic patients.84 The synthesis of bone and its mineralization depend on the calcium environment. Osteoporotic patients have a diminished pool of rapidly soluble calcium, inadequate dietary calcium, and a deficient structural calcium bone reserve.61 Calcium mineralization is subject to delay, and the stage of remodeling is prolonged because of competition for ionized calcium with the rest of the body. Also, substances that may have been mobilized to maintain systemic calcium homeostasis (PTH and vitamin D) may compromise the latter stages of fracture repair. In addition, up to 40% of elderly patients are mildly to moderately malnourished, and this condition compromises bone collagen synthesis.81 Bone scans remain positive (indicating continued metabolic remodeling) well into the third year after fracture in elderly persons, and union cannot be fully ascertained until that time.25 Studies have demonstrated that osteoporotic rats have delayed healing. It is uncertain whether it is the osteoporosis or the estrogen deficiency that compromises fracture repair.72, 106 Systemic bone loss occurs in the unaffected skeleton after long bone fractures, even when the patient has adequate calcium intake.103 Osteoporotic patients, who are typically chronically calcium deficient, may be more affected. Ideally, healing could be stimulated in such patients by physiologic levels of vitamin D (400 to 800 IU/day) and calcium (1500 mg of elemental calcium per day), normal nitrogen balance, and appropriate exercise.79
DEFINITION AND DIAGNOSIS
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is defined as a disease of decreased bone mass and changes in the microarchitecture of the skeleton. The disease may be recognized clinically in one of three ways: acute fracture (most commonly of the wrist, ribs, hip, or spine), asymptomatic thoracic wedge or lumbar compression fracture, or generalized osteopenia on a radiograph. More than 65% of individuals presenting with compression fractures are asymptomatic.35 Critical determinations are the cause and the extent of bone loss. A
diagnosis of osteopenia must differentiate among bone marrow disorders, endocrinopathy, osteomalacia, and osteoporosis.5, 79 The workup for osteopenia involves invasive and noninvasive methods. Operational definitions of osteopenia and osteoporosis are based on bone mass and density. Noninvasive techniques of determining osteopenia are used to quantitate bone mass and evaluate the efficacy of treatment. The simple radiograph is fraught with technical difficulty and may not identify osteopenia until 30% of the bone mass has been lost.49 Current methodology centers on dualphoton absorptiometry, quantitative computed tomography (CT), and ultrasonography. Dual-energy x-ray absorptiometry (DEXA) utilizes two energy levels.33, 58, 98 It permits correction for soft tissue and allows direct measurement of total bone mass (cortical and trabecular) within a specified amount of mineralized tissue of an aerial section of the spine or hip; the measurements are analyzed and expressed as grams per centimeter squared. Radiation is low (5 mrad) and precision (1% in the spine, 3% to 4% in the hip) and accuracy (4% to 6%) are good. Compression fractures, osteophytes, degenerative changes, and vascular calcifications can elevate local readings. A lumbar lateral radiograph is needed to correct for these artifacts. After the density has been calculated, comparisons can be made with age-matched peers (Z score) and with an adult population with peak bone mass (T score). A bone mass within 1 standard deviation is considered healthy. Osteopenia is defined between 1 and 2.4 standard deviations below peak bone mass. A bone mass 2.5 standard deviations below peak mass is considered frank osteoporosis. Individuals with a bone mass more than 1.5 standard deviations below that of their peers probably have a secondary cause of osteoporosis that must be evaluated. Alternative methods are also used to determine bone mass. CT is used to measure the midportion of the vertebral body and determine trabecular bone mass against a simultaneous phantom; in this way, it can be used to measure trabecular bone mass directly. It uses 20 times as much radiation and has poorer precision than DEXA.34 Ultrasonography is used to examine the heel, patella, tibia, and peripheral sites and measure several properties of bone; these measurements have a correlation of 0.75 with central density readings.100 As discussed previously, these noninvasive methods cannot clearly identify absolute fracture risk, but they can be used as a loose guide for management grouping and as an exacting tool for long-term determination of treatment efficacy. There are also markers of skeletal metabolic activity. Bone formation markers are bone-specific alkaline phosphatase and osteocalcin. Alkaline phosphatase rises within 5 days after a fracture is sustained. If the level is elevated at the time of fracture, it is due to a high-turnover state until proved otherwise. Hyperparathyroidism and osteomalacia must be considered in the workup. Bone collagen breakdown products can be used to measure bone turnover. Collagen molecules in the bone matrix are staggered to form fibrils that are joined by covalent crosslinks consisting of hydroxylysyl-pyridinoline (pyridinoline, Pyd) and lysyl-pyridinoline (deoxypyridinoline, Dpd). Dpd has greater specificity because Pyd is present in other connective tissues. Dpd and Pyd are linked to
Copyright © 2003 Elsevier Science (USA). All rights reserved.
430
SECTION I • General Principles
collagen where two aminotelopeptides (N-telopeptides [NTX] and C-telopeptides) are linked to a helical site and are released with Dpd and Pyd during osteoclastic bone resorption. These products are released into the circulation, metabolized by the liver and kidney, and excreted in the urine. Clinical applications of these markers include monitoring effectiveness of therapy,32 prediction of fracture risk,31 and selection of patients for antiresorptive therapy.12 NTX and DEXA provide highly sensitive, commonly used indices of metabolic activity and bone mass in clinical practice.73 High-turnover states such as hyperparathyroidism are characterized by high NTX levels. Osteoporosis (as determined by DEXA) has been divided into high turnover (high NTX) related to increased osteoclast activity and low turnover (low NTX) related to low osteoclast activity.73 No signs, symptoms, or diagnostic tests are specific for osteoporosis. In one study, 31% of osteoporotic women were found to have disorders with possible effects on skeletal health without major risk factors for postmenopausal osteoporosis.13 An algorithm for the diagnosis of osteopenia has been developed (Table 17–3). When osteopenia has been defined and localized bone disorders have been eliminated, the differential workup commences. First, a hematologic profile, serum protein electrophoresis, and biochemical profile studies are obtained. In common bone marrow disorders, including leukemia and myeloma (which together account for 1% to 2% of cases of osteoporosis), the bone marrow screen is usually abnormal (anemia, low white blood cell count, or low platelet count). A biochemical panel provides information on renal and hepatic function, primary hyperparathyroidism (high serum calcium), and possible malnutrition (anemia, low calcium, low phosphorus, or low albumin). If the bone marrow screen is negative, the diagnostic testing then centers on endocrinopathies. Premature menopause, iatrogenic Cushing’s disease, and type I diabetes mellitus are diagnosed by history. Determinations of PTH and thyroid-stimulating hormone identify hyperparathyroidism and hyperthyroidism. The latter may occur as osteoporosis and severe weight loss or as iatrogenic
hyperthyroidism, caused by overuse of thyroid replacement hormone medication by obese patients to control weight.80 Malnutrition is common in osteoporotic patients. Osteomalacia occurs in 8% of osteopenic patients in northern areas and may be identified by low levels of 25-hydroxyvitamin D, high secondary PTH, high alkaline phosphatase, low urinary calcium, low serum phosphorus, and low to normal serum calcium values. The mild hyperosteoidosis and lag in mineralization are often indistinguishable from those seen in osteoporosis by laboratory studies. The critical diagnostic study used to differentiate osteomalacia from osteoporosis is the transileal bone biopsy and histomorphometric analysis of the undecalcified bone.65 These studies permit a definitive diagnosis. If cost containment were not an issue, bone densitometry would be readily available to almost all postmenopausal women. Medicare now covers DEXA for estrogendeficient women older than 65 years. A cost-effectiveness analysis supported by the National Osteoporosis Foundation concluded that it is worthwhile to measure bone density in any woman with a vertebral fracture and in all white women older than 60 to 65 years. In healthy postmenopausal women between 50 and 60 years old, indications for DEXA include a history of low-trauma fracture, weight under 127 pounds, smoking, or a family history of an osteoporotic fracture.24 Most experts also agree that any patients with secondary causes of known bone loss should have their bone density measured.
MEDICAL TREATMENT AND PREVENTION
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is a heterogeneous disease of multifactorial causes. The principles of medical management necessitate decisions about whether bone mass should be maintained or augmented. If the patient has crossed his or her fracture threshold, bone augmentation is required. However, if the
TABLE 17–3
Sequence for the Workup of the Most Common Forms of Osteomalacia
Complete blood count Erythrocyte sedimentation rate Serum protein electrophoresis Parathyroid hormone Thyroid-stimulating hormone History of type I diabetes History of steroid use Normal ↓ Calcium (serum-urine) Phosphorus (serum) Alkaline phosphatase Blood urea nitrogen 25-Hydroxyvitamin D Parathyroid hormone Transileal bone biopsy (?)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abnormal 1%–2% ↓ Normal Abnormal 15%–25% ↓ Normal
→
Bone marrow biopsy
Myeloma Leukemia Benign marrow disorder Hyperparathyroidism Hyperthyroidism Diabetes mellitus (type I) Cushing’s disease
→
Abnormal 8% ↓ Normal Osteoporosis
→
Osteomalacia
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures
431
trauma level was of sufficient magnitude, maintenance may be all that is needed, even after a fracture. A careful history of the cause of the fracture and a noninvasive measurement of bone mass are essential. Adequate levels of exercise,1, 21, 46, 59, 84 calcium,36, 40 and vitamin D (400 to 800 IU/day) maintain both cortical and trabecular bone mass except in the early postmenopausal spine, when the loss is 2% per year. Physiologic levels of calcium intake, as determined by a National Institutes of Health consensus conference in 1994, are 1200 to 1500 mg/day from age 12 to 24 years, 1000 mg/day from age 25 years until menopause, and 1500 mg/day after menopause.83 Currently, bisphosphonates (alendronate and risedronate), raloxifene, and calcitonin are approved for treatment and low-dose alendronate and raloxifene are approved for prevention of osteoporosis. The Food and Drug Administration has approved estrogen for prevention and management of osteoporosis. Only alendronate has been labeled specifically for men, and bisphosphonates have not been approved for premenopausal women, particularly because of pregnancy. A treatment program has been approved by the National Osteoporosis Foundation for patients at risk of fragility fracture.84 Treatment is recommended for any individual with a T score of −2.5 or a score of −1.5 with four major risk factors, and prevention is recommended for a patient with osteopenia. If an individual has a known vertebral fracture, the use of hormone replacement therapy, alendronate, or calcitonin is recommended. For a patient without fracture and unwilling to consider treatment, physiologic calcium levels, vitamin D (400 to 800 units per day), exercise, and smoking cessation are recommended. Calcium, smoking cessation, and exercise are recommended for postmenopausal patients younger than 65 years without risk factors. These recommendations were made with Food and Drug Administration approval of estrogen for the treatment of osteoporosis; new treatment guidelines need to be established because the new labeled use of estrogen is for the prevention and management of osteoporosis.
is indicated only for prevention and management of osteoporosis, because long-term randomized control studies have not been performed to determine whether estrogen is an effective long-term fracture prevention treatment for osteoporosis.
Raloxifene
A series of synthetic estrogen-like modulators have been developed. These agents can compete with estrogen binding sites and seem to function more like an estrogen at bone and work effectively as antiresorptive agents. They are indicated for prevention of osteoporosis and treatment of vertebral fractures. Tamoxifen was used as an antiestrogen, particularly for patients with breast cancer. Bone cells are also responsive to tamoxifen.88 Individuals taking tamoxifen have 70% of the benefit of estrogen in terms of maintaining bone mass.15 It is not used as an antiosteoporotic agent because 70% of women have significant postmenopausal symptoms and a high incidence of uterine cancer. Raloxifene, a newer agent, is not associated with an increased incidence of uterine cancer, and early data suggest that there is a decreased risk of breast cancer in patients using raloxifene compared with control subjects.22 A trial comparing tamoxifen and raloxifene in preventive action against breast cancer is under way.18 Raloxifene is approved for the prevention of osteoporosis. Raloxifene can decrease the risk of vertebral fracture by approximately 40% to 50%, but there is no reported protection for the hip.28 Adverse effects include an 8% incidence of leg cramps and an increased risk of thrombophlebitis comparable with that associated with estrogen. It is not recommended in the first 5 years of menopause because it enhances postmenopausal symptoms.
Estrogen
Estrogen* has been the most studied and used drug for the prevention of osteoporosis. Epidemiologic studies, cohort and case-control, indicated that estrogen administration to postmenopausal women decreased skeletal turnover (25% to 50%) and the rate of bone loss in women 6 months to 3 years after menopause.12, 74 A large, longitudinal cohort study of 9704 postmenopausal women 65 years of age and older found that estrogen use was associated with a significant decrease in wrist fracture (relative risk [RR], 0.39) and of all nonspinal fractures (RR, 0.66). It appears to reduce risk of hip fractures by 20% to 60%.9 To prevent up to a ninefold increase in the probability of uterine cancer with estrogen alone, estrogen should be cycled with progesterone. Estrogen may not provide cardiac protection, and it increases the risk for breast cancer (by as much as 30%).2, 6, 42, 86 Currently, estrogen
*See references 6, 10, 28, 29, 44, 45, 57, 70, 71, 104, 105.
Calcitonin
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid. It may play a role in the skeletal development of the embryo and fetus, but its primary action is on bone to reduce osteoclastic bone resorption by diminution of osteoclasts (shrinkage of cells, loss of ruffled border, reduction in resorptive activity, and increased apoptosis).11 It has been effectively used in patients with hypercalcemia, Paget’s disease, and osteoporosis. It is indicated for the treatment of postmenopausal women more than 5 years after menopause with low bone mass compared with healthy premenopausal women. A nasal form of calcitonin at a dosage of 200 units per day appears to increase bone mass in the spine and decrease spinal fractures by 37%. To date, there has been no benefit in hip fracture prevention.8, 85 Calcitonin does have another benefit of providing some analgesia. It has been used in patients with painful osteoporotic fractures and does not interfere with fracture healing.89 The only established side effect is rhinitis (23% versus 7% for placebo).26
Copyright © 2003 Elsevier Science (USA). All rights reserved.
432
SECTION I • General Principles
Bisphosphonates
Bisphosphonates are stable, active analgesics of pyrophosphate68 that inhibit osteoclastic resorption and depress bone turnover27, 49, 58, 87 by binding to the osteoclastresorbing surface and acting as a nondegradable shield. When absorbed by the osteoclast, they inhibit osteoclast function. Bisphosphonates have low bioavailability, and less than 1% is absorbed orally. Alendronate is the first bisphosphonate approved for the treatment of osteoporosis. Low-dose alendronate, 5 mg/day or 10 mg three times a week, is approved for prevention of osteoporosis. It has been shown to increase bone mass in the hip and spine. It decreased the risk of all fractures by approximately 50% after 1 year of treatment.7, 17, 67 Regardless of the degree of bone mass enhancement, all patients treated with alendronate had equal protection against fractures, suggesting an improvement in bone quality. Alendronate has been associated with esophageal irritation, and as many as 30% of individuals have had esophagitis; in a carefully controlled study, the rate of esophagitis was comparable to that in the placebo group.67 Currently, a once-weekly dosage of 70 mg is as efficacious and produces significantly less indigestion. Risedronate, at 5 mg/day, is the second bisphosphonate approved for both prevention and treatment of osteoporosis. It has a profile similar to that of alendronate and may cause less esophageal irritation. It reduced the risk of new vertebral fractures by 49% over 3 years compared with a control group (P < .001), and the risk of nonvertebral fractures was reduced by 33% compared with a control group over 3 years (P = .06).96 Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of the placebo group.95 A head-to-head comparison of the two agents has not been performed. Bisphosphonates have a long-lasting effect on bone. A double-blind, multicenter study of postmenopausal women101 (at least 2.5 standard deviations below the peak premenopausal mean) compared the efficacy and safety of treatment with oral once-weekly alendronate at 70 mg (n = 519), twice-weekly alendronate at 35 mg (n = 369), and daily alendronate at 10 mg (n = 370) for 1 year. Increases in bone density of the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly showed reduced biochemical markers of bone resorption (urinary Ntelopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) in the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal adverse experiences. There were fewer serious upper gastrointestinal adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared with the daily dosing group. This study suggests that once-weekly dosing of bisphosphonates may provide a more convenient, therapeutically equivalent alternative to daily dosing. Pamidronate has not been approved for treating osteoporosis but is used for treating patients with metastatic disease, hypercalcemic malignancy, and Paget’s
disease. At our institution, The Hospital for Special Surgery in New York, intravenous doses of pamidronate have been successful in treating osteoporosis in this population. A combination regimen of alendronate and estrogen has been studied. A randomized controlled trial indicated that a combination of alendronate and estrogen was superior to the single agents in terms of bone density augmentation.69
MANAGEMENT OF OSTEOPOROTIC FRACTURES
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The impact of skeletal loss becomes most apparent as the skeleton begins to fail in its ability to withstand normal loads. When the skeleton no longer functions structurally, osteoporosis becomes a disease state. The overriding goal of management of fractures in the osteoporotic patient is to achieve early and definitive stabilization of the injured extremity. At The Hospital for Special Surgery in New York, an osteoporosis treatment center has been established. The experiences derived from management in a large combined population have given rise to the following treatment principles and protocols: 1. Elderly patients are best served by rapid, definitive fracture care that allows early mobilization. In the patient with concurrent illnesses or markedly abnormal laboratory results, medical evaluation and stabilization of reversible medical decompensations should be performed before surgery.35 In most cases, patients are at their respective homeostatic optimum on the day of injury and should ideally be treated with surgery at that time. 2. Surgical treatment is directed at achieving stable fracture fixation and early return of function. In the lower extremity, this implies early weight bearing. Anatomic restoration is important in intra-articular fractures, whereas stability is the goal in the treatment of metaphyseal and diaphyseal fractures. 3. Surgical procedures are designed with an effort to minimize operative time, blood loss, and physiologic stress. 4. Osteoporotic bone, with its decreased density, lacks the strength to hold screws and plates securely and more often involves comminution.8 As a result, failure of internal fixation is caused primarily by bone failure rather than by implant failure. Internal fixation devices are chosen that allow impaction of the fracture fragments into stable patterns that minimize the load carried by the implants. In addition, implants that minimize stress shielding are chosen to prevent further skeletal decompensation of the involved bone. For these reasons, sliding nail plate devices and intramedullary devices that are load sharing and allow fracture compression are the devices of choice. 5. Because most of these fractures are related to underlying metabolic bone disease, a full evaluation of the etiologic condition is performed and an appropriate
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures
433
medical therapeutic program is developed for each patient. 6. An inadequate calcium intake could result in deficits in callus mineralization or remodeling.25 Because many elderly patients are malnourished, nutritional assessment should be included in the patient’s evaluation. The specific management of fractures about the knee and of Colles’, hip, spine, proximal humeral, and pelvic fractures is discussed elsewhere in appropriate chapters. This chapter includes a discussion of the femoral neck fracture because of its strong implications for metabolic bone disease. A series of studies from the fracture service at New York Hospital99 demonstrated that 8% of patients with femoral neck fracture had frank osteomalacia. Although 40% had marked trabecular bone loss (less than 15% trabecular bone volume, with normal being more than 22%), all patients older than 50 years had some reduction of bone mass when compared with younger persons. Twenty-five percent had increased metabolic turnover indices, including a high osteoclast count. In the series of Scileppi and colleagues,101 bone histomorphometry appeared to be a good predictor of outcome after treatment for femoral neck fracture.61 Patients who had trabecular bone volume that was within 60% of normal (i.e., volume higher than 15%) had an 85% to 95% rate of successful union, whereas for patients who had severe trabecular bone loss (to less than 15% of bone volume) the rate was lower than 33% in women and lower than 50% in men. These combined studies at New York Hospital suggest that significant metabolic bone disease, particularly osteoporosis, leads to a high rate of unsuccessful union after femoral neck fracture. Comparable studies of other fractures commonly associated with osteoporosis are lacking, but presumably osteoporosis per se affects the type, severity, and repair process in these fractures as well. Application of the outcome studies of femoral neck fractures in relation to osteopenia has resulted in specific protocols at The Hospital for Special Surgery and the New York Presbyterian Hospital. Our current protocol for treatment of a displaced femoral neck fracture in the ambulatory patient who is physiologically younger than 65 years relies on closed reduction and stable internal fixation using the sliding compression screw or cannulated screws as the primary form of treatment. If stability cannot be achieved, the patient is treated with a hemiarthroplasty. The ambulatory patient who is physiologically older than 70 years is treated by hemiarthroplasty. Closed reduction and pinning are the method of choice in caring for the nonambulatory patient. Patients with severe demineralizing bone disease (marked osteoporosis), pathologic fractures secondary to metastasis, or neurologic disorders that require immediate ambulation and patients who cannot comply with physical therapy regimens requiring partial weight bearing are treated with primary hemiarthroplasty. Traditionally, treatment of vertebral compression fractures consists of medical pain management. In 1984, vertebroplasty, structural reinforcement of the vertebral body with polymethylmethacrylate cement, was first used in the treatment of osteoporotic vertebral fractures. The primary indication for vertebroplasty is pain relief. The procedure is performed under local or general anesthesia
and a transpedicle or extrapedicle approach is used to reach the anteroinferior border of the vertebral body. In vertebroplasty, radiodense polymethylmethacrylate cement is injected into the vertebral body under high pressure using Luer-Lok syringes in 2- to 3-ml allotments. Several cohort studies reported a decrease in pain in 80% to 90% of patients, a complication rate of 5% to 6%, and no fracture reduction.4, 23, 47 Kyphoplasty is a similar procedure designed to provide significant pain relief, rapid return to activities of daily living, restoration of vertebral body height, and reduction in spinal deformity. In this procedure, a balloon tamp is inserted into the center of the collapsed vertebral body and inflated with radiopaque liquid under fluoroscopic guidance. The patient is continually monitored by sensory evoked potential for neural damage throughout the procedure at The Hospital for Special Surgery. The balloon strikes cancellous bone circumferentially around the tamp and thereby reduces the deformation and restores height to the vertebral body. The balloon is deflated and removed, and the cavity is filled with the surgeon’s choice of biomaterial, stabilizing the fracture. Approximately 1000 fractures in 600 patients have been treated by this technique. A review of 226 kyphoplasties in 121 patients63 found that 96% of patients had pain relief as determined using a pain analogue scale. There was 45% restoration of height in the anterior plane, 71% at the midline, and 54% posteriorly. In this series, there was one case of epidural bleeding requiring decompression, one incomplete spinal injury, and one report of transient adult respiratory distress syndrome. No episodes of infection, pulmonary emboli, or myocardial infarction have been reported. In this study, the average age was 73.7 years and each patient had on average 3.7 co-morbidities. A quality-of-life questionnaire (called SF-36) was administered to patients before and after kyphoplasty.69a The questionnaire is standardized and validated and is designed to assess functional status and well-being. The questions are used to calculate summary measures of physical and mental health such as bodily pain and physical function. The summary measures are then normalized to a scale of 1 to 100, where 1 is the lowest score and 100 is the highest or best score. In these patients, both bodily pain and physical function scores improved significantly (P < .004 for bodily pain, P < .02 for physical function) when assessed 1 week after kyphoplasty. These preliminary data suggest that kyphoplasty is an effective, minimally invasive technique for providing pain relief and restoration of vertebral height.
REFERENCES 1. Aloia, J.E.; Cohn, S.H.; Ostuni, J.A.; et al. Prevention of involutional bone loss by exercise. Ann Intern Med 89:356, 1978. 2. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med 117:1038, 1992. 3. Avioli, L.V. Postmenopausal osteoporosis: Prevention vs. cure. Fed Proc 40:2418, 1981. 4. Barr, J.D.; Barr, M.S.; Lemley, T.J.; McCann, R.M. Percutaneous vertebroplasty for pain relief and spinal stabilization. Spine 25:923, 2000.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
434
SECTION I • General Principles 30. Frost, H.M. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res 3:211, 1969. 31. Garnero, P.; Hausherr, E.; Chapuy, M.C.; et al. Markers of bone resorption predict hip fracture in elderly women: The EPIDOS prospective study. J Bone Miner Res 11:1531, 1996. 32. Garnero, P.; Shih, W.J.; Gineyts, E.; et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693, 1994. 33. Genant, H.K.; Boyd, D.P. Quantitative bone mineral analysis using dual energy computed tomography. Invest Radiol 12:545, 1977. 34. Glaser, D.L.; Kaplan, F Osteoporosis: Definition and clinical .S. presentation. Spine 22(Suppl 24):12S, 1997. 35. Glimcher, M.A. On the form and structure of bone from molecules to organs: Wolff’s law revisited. In: Veis, A., ed. The Chemistry and Biology of Mineralized Tissues. New York, Elsevier–North Holland, 1982, p. 613. 36. Greenspan, S.L.; Myers, E.R.; Maitland, L.A.; et al. Fall severity and mineral density as risk factors for hip fracture in ambulatory elderly. JAMA 271:128, 1994. 37. Hakkinen, K. Force production characteristics of leg extensor, trunk flexor, and extensor muscles in male and female basketball players. J Sports Med Phys Fitness 31:325, 1991. 38. Hansen, M.A.; Overgaard, K.; Riss, B.J.; Christiansen, C. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 303:1548, 1991. 39. Hayes, W.C.; Myers, E.R.; Morris, J.N.; et al. Impact near the hip dominates fracture risk in elderly nursing home residents who fall. Calcif Tissue Int 52:192, 1993. 40. Heaney, R.P. Effect of calcium on skeletal development, bone loss, and risk of fractures. Am J Med 91:23S, 1991. 41. Heaney, R.P. Nutrition and Osteoporosis. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 270. 42. Hemminki, E.; Topo, P.; Malin, M.; Kangas, I. Physician’s views on hormone therapy around and after menopause. Maturitas 16:163, 1993. 43. Holbrook, T.; Grazier, K.; Kelsey, J.; et al. The frequency of occurrence, impact and cost of selected musculoskeletal conditions in the United States. Chicago, Ill.: American Academy of Orthopedic Surgeons, 1984. 44. Horseman, A.; Gallagher, J.C.; Simpson, M.; et al. Prospective trial of oestrogen and calcium in postmenopausal women. BMJ 2:789, 1977. 45. Hutchinson, T.A.; Polansky, S.M.; Feinstein, A.R. Postmenopausal oestrogens protect against fractures of hip and distal radius: A case control study. Lancet 2:705, 1979. 46. Jacobsen, P.C.; Beaver, W.; Grubb, S.A.; et al. Bone density in women; college athletes and older athletic women. J Orthop Res 2:328, 1984. 47. Jansen, M.E.; Evans, A.J.; Mathis, J.M.; et al: Percutaneous polymethylmethacrylate vertebroplasty in the treatment of osteoporotic vertebral body compression fractures: Technical aspects. AJNR 18:1897, 1997. 48. Johnson, T.R.; Tomin, E.; Lane, J.M. Perspectives on growth factors, bone graft substitutes and fracture healing. In: Obrant, K., ed. Management of Fractures in Severely Osteoporotic Bone. London, Springer, 2000, p. 111. 49. Johnston, C.C., Jr.; Epstein, S. Clinical, biochemical, epidemiologic, and economic features of osteoporosis. Orthop Clin North Am 12:559, 1981. 50. Jones, B.H.; Bovee, M.W.; Harris, J.M.; et al: Intrinsic risk factors for exercise-related injuries among male and female army trainees. Am J Sports Med 21:705, 1993 51. Jones, B.H.; Cowan, D.N.; Tomlinson, J.P.; et al: Epidemiology of injuries associated with physical training among young men in the army. Med Sci Sports Exerc 25:197, 1993. 52. Jowsey, J. Bone morphology: Bone structure. In: Sledge, C.B., ed. Metabolic Disease of Bone. Philadelphia, W.B. Saunders, 1977, pp. 41–47. 53. Juppner, H.; Brown, E.M.; Kronenberg, H.M. Parathyroid hormone. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 80.
5. Barth, R.W.; Lane, J.M. Osteoporosis. Orthop Clin North Am 19:845, 1988. 6. Belchetz, P.E. Hormonal treatment of postmenopausal women. N Engl J Med 330:1062, 1994. 7. Black, D.M.; Cummings, S.R.; Karph, D.B.; et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535, 1996. 8. Cardona, J.M.; Pastor, E. Calcitonin versus etidronate for the treatment of postmenopausal osteoporosis: A meta-analysis of published clinical trials. Osteoporos Int 7:165, 1997. 9. Carter, D.R.; Hayes, W.C. The compressive behavior of bone as a two-phase porous structure. J Bone Joint Surg Am 59:954, 1977. 10. Cauley, J.A.; Seeley, D.G.; Ensrud, K.; et al. Estrogen replacement therapy and fractures in older women: Study of Osteoporosis Research Group. Ann Intern Med 122:9, 1995. 11. Chambers, T.J.; Moore, A. The sensitivity of isolated osteoclasts to morphological transformation by calcitonin. J Clin Endocrinol Metab 57:819, 1983. 12. Chesnut, C.H., III; Bell, N.H.; Clark, G.S.; et al. Hormone replacement therapy in postmenopausal women: Urinary Ntelopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med 102:29, 1997. 13. Clark, J.; Tamenbaum, C.; Posnett, K.; et al. Laboratory testing in healthy, osteopenic women. J Bone Miner Res 12:S141, 1997. 14. Compston, J.E. Connectivity of cancellous bone: Assessment and mechanical implications. Bone 15:63, 1994. 15. Cosman, F Lindsay, R. Selective estrogen receptor modulators: .; Clinical spectrum. Endocr Rev 20:418, 1999. 16. Courtney, A.C.; Washtel, E.F Myers, E.R.; Hayes, W.C. Age-related .; reductions in the strength of the femur tested in a fall-loading configuration. J Bone Joint Surg Am 77:387, 1995. 17. Cummings, S.R.; Black, D.M.; Thompson, D.E.; et al. Effect of alendronate on risk of fracture in women with low bone density by without vertebral fractures. JAMA 280:2077, 1998. 18. Cummings, S.R.; Eckert, S.; Kreuger, K.A.; et al. The effects of raloxifene on the risk of breast cancer in postmenopausal women: Results from the MORE (Multiple Outcome of Raloxifene Evaluation) randomized trial. JAMA 281:2189, 1999. 19. Cummings, S.R.; Kellsey, J.L.; Nevitt, M.C.; O’Dowd, K.J. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178, 1985. 20. Cummings, S.R.; Nevitt, M.C.; Browner, W.S.; et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767, 1995. 21. Dalsky, G.P.; Stocke, K.S.; Ehsani, A.A.; et al. Weight-bearing exercise training and lumbar bone mineral content in postmenopausal women. Ann Intern Med 108:824, 1988. 22. Delmas, P.D.; Bjarnason, N.H.; Mitlak, B.H.; et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641, 1997. 23. Deramond, H.; Darrason, R.; Galibart, P. Percutaneous vertebroplasty with acrylic cement in the treatment of aggressive spinal angiomas. Rachis 1:143, 1989. 24. Eddy, D.M.; Cummings, S.R.; Johnson, C.C.; et al. Osteoporosis: Review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis. Osteoporos Int 8:S1, 1998. 25. Einhorn, T.A.; Bonnarens, F Burstein, A.H. The contributions of .; dietary protein and mineral to the healing of experimental fractures: A biomechanical study. J Bone Joint Surg Am 68:1389, 1986. 26. Ellerington, M.C.; Hillard, T.C.; Whitcroft, S.I.J.; et al. Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis. Calcif Tissue Int 59:6, 1996. 27. Endo, Y.; Nakamora, M.; Kikuchi, T.; et al. Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo. Calcif Tissue Int 52:248, 1993. 28. Ettinger, B; Black, D.M.; Mitlak, B.H.; et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a three year randomized clinical trial. JAMA 282:637, 1999. 29. Ettinger, B.; Genant, H.K.; Cann, C.E. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 102:319, 1985.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures 54. Kelsey, J.F Osteoporosis: Prevalence and incidence. In: Proceedings . of the NIH Consensus Development Conference, April 22, 1984. Bethesda, MD, National Institutes of Health, 1984, p. 25. 55. Kempson, G. The mechanical properties of articular cartilage and bone. In: Owen, R.; Goodfellow, J.; Bullough, P., eds. Scientific Foundations of Orthopaedics and Traumatology. Philadelphia, W.B. Saunders, 1980, p. 49. 56. Kenzora, J.E.; McCarthy, R.E.; Lowell, J.D.; Sledge, C.C. Hip fracture mortality: Relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop 186:45, 1985. 57. Kiel, D.P.; Felson, D.T.; Anderson, J.J.; et al. Hip fracture and the use of estrogens in postmenopausal women. N Engl J Med 317:1169, 1987. 58. Kimmel, P.L. Radiologic methods to evaluate bone mineral content. Ann Intern Med 100:908, 1984. 59. Krolner, B.; Toft, B.; Pors Nielsen, S.; et al. Physical exercise as a prophylaxis against involutional vertebral bone loss: A controlled trial. Clin Sci (Colch) 64:541, 1983. 60. Lane, J.M.; Vigorita, V.J. Osteoporosis. Orthop J 1:22, 1985. 61. Lane, J.M.; Cornell, C.N.; Healey, J.H. Orthopaedic consequences of osteoporosis. In: Riggs, B.L.; Melton, L.J., III, eds. Osteoporosis: Etiology, Diagnosis and Management. New York, Raven Press, 1988, p. 111. 62. Lane, J.M.; Werntz, J.R. Biology of fracture healing. In: Lane, J., ed. Fracture Healing. New York, Churchill Livingstone, 1987, p. 49. 63. Lane, J. M.; Girardi, F Parvataneni, H.; et al. Preliminary outcomes .; of the first 226 consecutive kyphoplasties for the fixation of painful osteoporotic vertebral compression fractures. Paper presented at the World Congress on Osteoporosis 2000, June 2000. 64. Lane, J.M. Metabolic bone disease and fracture healing. In: Heppenstall, R.B., ed. Fracture Treatment and Healing. Philadelphia, W.B. Saunders, 1980, p. 946. 65. Lane, J.M.; Vigorita, V.J.; Falls, M. Osteoporosis: Current diagnosis and treatment. Geriatrics 39:40, 1984. 66. Lane, J.M.; Healey, J.H.; Schwartz, E.; et al. The treatment of osteoporosis with sodium fluoride and calcium: Effects on vertebral fracture incidence and bone histomorphometry. Orthop Clin North Am 15:729, 1984. 67. Lane, J.M.; Russell, L.; Khan, S.N. Osteoporosis. Clin Orthop 372:139, 1999. 68. Leiberman U.A.; Weiss S.R.; Broll J.; et al. Effect of oral alendronate on bone mineral density and the incidence of fracture in postmenopausal osteoporotic women. N Engl J Med 333:1437, 1995. 69. Lian, J.B.; Stein, G.S.; Canalis E.; et al. Bone formation: Osteoblast lineage cells, growth factors, matrix proteins, and the mineralization process. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 14. 69a. Lieberman, I.; Dudeney, S.; Reinhardt, M-K.; Bell, G. Initial outcome and efficacy of kyphoplasty in the treatment of painful osteoporosis vertebral compression fractures. Spine 26:1631, 2001. 70. Lindsey, R.; Bush, T.L.; Lobo, R.A.; et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis. A randomized controlled trial. J Clin Endocrinol Metab 84:3078, 1999. 71. Lindsey, R.; Hart, D.M.; Aitken, J.M.; et al. Long-term prevention of postmenopausal osteoporosis by estrogen. Lancet 1:1038, 1976. 72. Lindsey, R.; Hart, D.M.; Aitken, J.M.; et al. Prevention of spinal osteoporosis in oophorectomised women. Lancet 2:1151, 1980. 73. Lindsey, R.; Hart, D.M.; MacLean, A. Bone response to termination of oestrogen treatment. Lancet 1:1325, 1978. 74. Loucks, A.B.; Motorola, J.F Girton, L.; et al: Alterations in the .; hypothalamic-pituitary-ovarian and the hypothalamic-pituitaryadrenal axis in the athletic woman. J Clin Endocrinol Metab 68:402, 1989. 75. Lufkin, E.G.; Wahner, H.W.; O’Fallon, W.M.; et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 117:1, 1992. 76. Melton, L.J., III; Riggs, B.L. Epidemiology of age-related fractures. In: Avioli, L.V., ed. The Osteoporotic Syndrome: Detection, Prevention and Treatment. Orlando, FL, Grune & Stratton, 1983, p. 45. 77. Melton, L.J., III; Riggs, B.L. Epidemiology of age-related fractures. In: Avioli, L.V., ed. The Osteoporotic Syndrome. New York, Grune & Stratton, 1987, pp. 1–30.
435
78. Melton, L.J.I.; Khosla, S.; Atkinson, E.J.; et al. Relationship of bone turnover to bone density and fractures. J Bone Miner Res 12:1083, 1997. 79. Meunier, P.J. Prevention of hip fractures. Am J Med 95:755, 1993. 80. Mohler, D.G.; Lane, J.M.; Cole, B.J.; Winerman, S.A. Skeletal fracture in osteoporosis. In: Lane, J.M.; Healey, J.H., eds. Diagnosis and Management of Pathological Fractures. New York, Raven Press, 1993, p. 13. 81. Mosekilde, L.; Eriksen, E.F Charles, P. Effects of thyroid hormone .; on bone and mineral metabolism. Endocrinol Med Clin North Am 19:35, 1990. 82. Mullen, J.O.; Mullen, N.L. Hip fracture mortality: A prospective multifactorial study to predict and minimize death risk. Clin Orthop 280:214, 1992. 83. National Institutes of Health Consensus Development Conference Statement on Osteoporosis, Vol. 5, No. 3, 1984. JAMA 252:799, 1985. 84. NIH Consensus Conference. Optimal calcium intake. JAMA 272:1942, 1994. 85. National Osteoporosis Foundation. Osteoporosis: Review of the evidence for the prevention, diagnosis, and treatment and costeffectiveness analysis. Osteoporos Int 8:1, 1998. 86. Ott, S.M. Clinical effects of bisphosphonates in involutional osteoporosis. J Bone Miner Res 8(Suppl):597, 1993. 87. Overgaard, K.; Hansen, N.A.; Jensen, S.B.; et al. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis. A dose response study. Bone Miner 305:556, 1992. 88. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of estrogen on estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 273:199, 1995. 89. Powels, T.J.; Hicklish, T.; Kanis, J.A.; et al. Effect of tamoxifen on bone mineral density measured by dual energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 18:78, 1995. 90. Pun, K.K.; Chan, L.W. Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures. Clin Endocrinol (Oxf) 30:435, 1989. 91. Ray, N.F Chan, J.K.; Thamer, M.; et al. Medical expenditures for .; the treatment of osteoporotic fractures in the United States in 1995: Report from the National Osteoporosis Foundation. J Bone Miner Res 12:24, 1997. 92. Recker, R.R.; Kimmel, D.B.; Parfitt, A.M.; et al. Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res 3:133, 1988. 93. Riggs, B.L.; Melton, L.J., III. Evidence for two distinct syndromes of involutional osteoporosis. Am J Med 75:899, 1983. 94. Riggs, B.L.; Melton, L.J., III. Involutional osteoporosis. N Engl J Med 314:1676, 1986. 95. Riggs, B.L.; Melton, L.J., III. The prevention and treatment of osteoporosis. N Engl J Med 327:620, 1992. 96. Riginster, J.; Minne, H.W.; Sorsenson, O.H.; et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83, 2000. 97. Rosen, C.J.; Kiel, D.P. The aging skeleton. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 57. 98. Rubin, C.T.; Rubin, J. Biomechanics of bone. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 57. 99. Schneider, R.; Math, K. Bone density analysis: An update. Curr Opin Orthop 5:66, 1994. 100. Schnitzer, T.; Bone, H.G.; Crepaldi, G.; et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate OnceWeekly Study Group. Aging 12:1, 2000. 101. Scileppi, K.P.; Stulberg, B.; Vigorita, V.J.; et al. Bone histomorphometry in femoral neck fractures. Surg Forum 32:543, 1981. 102. Seeger, L.L. Bone density determination. Spine 22(Suppl 24):49S, 1997. 103. Shinoda, H.; Adamek, G.; Felix, R. Structure-activity relationships of various bisphosphonates. Calcif Tissue Int 35:87, 1983.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
436
SECTION I • General Principles Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 257. 109. Weiss, N.S.; Ure, C.L.; Ballard, J.H.; et al. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 303:1195, 1980. 110. World Health Organization. Assessment of fracture risk and its application to screening for post-menopausal osteoporosis: Report of a World Health Organization Study Group. World Health Organ Tech Rep Ser 843:1, 1994.
104. Silver, J.J.; Einhorn, T.A. Osteoporosis and aging: Current update. Clin Orthop 316:10, 1995. 105. Smith, R.W., Jr.; Walter, R.R. Femoral expansion in aging women: Implications for osteoporosis and fractures. Science 145:156, 1964. 106. Steier, A.; Gegalia, I.; Schwartz, A.; Rodan, A. Effect of vitamin D and fluoride on experimental bone fracture healing in rats. J Dent Res 46:675, 1967. 107. Walsh, W.R.; Sherman, P.; Howlett, C.R.; et al. Fracture healing in a rat osteopenia model. Clin Orthop 342:218, 1997. 108. Wasnich, R.D. Epidemiology of Osteoporosis. In: Favus, M.J., ed.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
17
Osteoporotic Fragility Fractures Osteoporotic Fragility Fractures
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Joseph M. Lane, M.D. Charles N. Cornell, M.D. Margaret Lobo, M.D. David Kwon, M.S.
EPIDEMIOLOGY
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is the most prevalent metabolic bone disease, affecting a large portion of the aging, predominantly female, population in the United States.108 On the basis of World Health Organization criteria, it is estimated that 15% of postmenopausal white women in the United States and 35% of women older than 65 years of age have frank osteoporosis.110 As many as 50% of women have some degree of low bone density in the hip. An estimated 1.2 million fractures annually are attributable to osteoporosis, including 538,000 vertebral, 227,000 hip, and 172,000 distal forearm (Colles’) fractures.54, 76, 94 Increasing age is significantly correlated with the incidence of fractures.77 Fractures in the wrist rise in the sixth decade, vertebral fractures in the seventh decade, and hip fractures in the eighth decade.107 One of every two white women experiences an osteoporotic fracture at some point in life.66 Among those who live to the age of 90 years, 32% of women and 17% of men sustain a hip fracture.75 Twenty-four percent of patients with hip fracture die within 1 year as a result; 50% require long-term nursing care, and only 30% ever regain their prefracture ambulatory status.18, 75, 78, 82 Of patients in nursing homes, 70% do not survive 1 year.3, 43, 44, 56, 60 The financial burden of osteoporosis is rapidly escalating as the population ages. Patients with fragility fractures create a significant economic burden. Treating osteoporosis is more costly than 400,000 hospital admissions and 2.5 million physician visits per year.109 Health care expenditures attributable to osteoporotic fractures were estimated as $13.8 billion, of which $10.3 billion was for the treatment of white women.90 The cost of acute and long-term care for osteoporotic fractures of the proximal femur alone has been estimated to exceed $10 billion annually in the United States.84 It is estimated that hip
fractures alone may cost the United States $240 billion in the next 50 years.107 These statistics indicate the need for increased physician awareness and diagnosis and, more important, emphasis on prevention of osteoporosis.
BONE AS A METABOLIC ORGAN
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The relation between metabolic bone disease and fracture healing depends on the role of the skeleton as a metabolic resource.62 Bone consists of a mineral fraction, hydroxyapatite crystals, and an organic fraction, largely (90%) type I collagen.79 The mineral fraction of bone makes up more than 98% of the body calcium.64 The bone, therefore, is the principal calcium reservoir of the body, and its specific architecture provides both structural support and an extensive bone surface for easy calcium mobilization. Bone is characterized as a composite material in which the collagen provides the tensile strength and hydroxyapatite the compressive strength.55 Bone is constantly renewing itself through a process of formation that is under cellular control.38 It is a dynamic connective tissue, and its responsiveness to mechanical forces and metabolic regulatory signals that accommodate requirements for maintaining the organ and connective tissue functions of bone are operative throughout life.68 The half-life of bone varies according to structural and metabolic demands. Bone formation is provided by osteoblast activity (measured by alkaline phosphatase and osteocalcin), and bone resorption is under osteoclast control (measured by N-telopeptides).79 The remodeling process and bone turnover appear to be coupled to and influenced by local humoral factors, biophysical considerations (Wolff’s law: ‘‘form follows function’’), and systemic demands.79 Vitamin D, parathy427
Copyright © 2003 Elsevier Science (USA). All rights reserved.
428
SECTION I • General Principles
roid hormone (PTH), and estrogen are among the hormones that control bone metabolism. Vitamin D, more specifically 1,25-dihydroxyvitamin D, is responsible for facilitating calcium absorption and osteoclastic resorption.41 Administration of PTH leads to the release of calcium from bone,53 and bone mass is directly related to the levels of estrogen in both men and women.98 Bone is primarily cortical (with a large volume and low surface area) or trabecular (with a large surface area and low volume). Because bone is resorbed and formed on surfaces, mainly the endosteal surface, trabecular bone, with its greater surface-to-volume ratio, is metabolically more active.50, 51, 61 The material properties of bone are, in large part, related to the microdensity of the material.9 Because the modulus of bone decreases only minimally with age, its primary strength is determined by its mass and structure.9, 52 The importance of structural distribution is evidenced by the greater bending and torsional strength of a tube compared with a rod of equal cross-sectional material area. Maximization of the moment of inertia (distribution of the mass away from the epicenter) in nature enhances the structural strength of bone, particularly when the mass is deficient. A 10% shift of bone outward can compensate for a 30% loss in bending and torque. In the aging human, loss of cortical bone mass is partially compensated by expansion of the diameter of the cortex. However, the increase in the diameter of long bones rarely exceeds 2% of the original diameter per year.30, 92 Therefore, the actual loss of cortical mass places elderly persons at an increasing risk of fracture. The structural strength is also related to connectivity—the degree of interconnection within bone.14, 91
MECHANISM OF OSTEOPENIC FRACTURE
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The composite structure of bone allows it to withstand compressive and tensile stresses as well as bending and torsional moments.97 Trabecular bone is often subjected to large impact stresses, whereas cortical bones often handle torque and bending. The vertebral body is largely protected by its trabecular bone, whereas the femoral neck depends on a mixture of cortical and trabecular bone for protection.9, 61 The hallmark of osteoporosis is deficient bone density and lack of connectivity.37, 73 The decreased bone mass associated with osteoporosis reduces the load-bearing ability of both cortical and trabecular bone, resulting in an increased risk of fracture. Areas of the skeleton rich in trabecular bone sustain the first consequences of osteoporosis; the trabecular bone is thinner in dimension and shows evidence of osteoclastic resorption, leading to disconnectivity of the trabecular elements.66 Trabecular bone is resorbed at a higher rate (8% per year) than cortical bone (0.5% per year) after menopause. Riggs and Melton93 recognized this discrepancy and developed the concept of two forms of osteoporosis with separate fracture patterns. Type I postmenopausal osteoporosis primarily affects women 55 to 65 years of age, is related to estrogen deficiency, results principally in trabecular bone loss, and is
manifest in spinal fractures. Type II senile osteoporosis affects both men and women (1:2 ratio) 65 years of age or older, is related to chronic calcium loss throughout life, results in cortical bone loss, and induces long bone fractures. Although bone mass is clearly related to fracture risk, a true fracture threshold can only be implied. Structure, fall tendency and type, ability of microfractures to heal before they become macrofractures, quality of bone, and such ill-defined factors as aging all play a role in fracture risk.1 The overlap of mass determination precludes clearly defining persons at absolute risk. Even at the lowest bone mass measurements, a percentage of individuals are free of fracture (Tables 17–1 and 17–2). For patients with hip fractures, Riggs and Melton93 demonstrated a fourfold increase in fracture rate with a 50% decrease in bone mass. The exponential increase in fracture rate with loss of bone mass is in agreement with the laboratory structural data of Carter and Hayes.9 Bone loss places the aging individual at greater risk of fracture, and fracture treatment therefore should include a bone maintenance strategy (see later discussion). Greenspan and co-workers36 documented etiologic factors for hip fractures in addition to bone density, including falls to the side, lower body mass index, and a higher potential to fall.39 Courtney and colleagues16 showed that the femur of an elderly person has half the strength and half the energy absorption capacity of the femur of a younger person. Falls from standing height exceed femoral breaking strength by 50% in elderly people but are below femoral fracture strength by 20% in the young. Cummings and associates19 included as hip fracture risks, in addition to low bone mass, aging, history of maternal hip fracture, tallness, lack of weight gain with aging, poor health, previously treated hypothyroidism, use of benzodiazepines, use of anticonvulsant drugs, lack of walking for exercise, lack of unsupported standing for 4 hours a day, a resting pulse rate higher than 80 beats per minute, and a history of any fracture after the age of 50 years. If two of these factors are present, 1 in 1000 individuals sustain a hip fracture in a given year. If five or more hip fracture risk factors are present in a patient who also has a low bone mass, the risk rises to 27 in 1000 individuals per year.20
FRACTURE HEALING AND OSTEOPOROSIS
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Normal fracture healing is a specialized process in which structural integrity is restored through the regeneration of
TABLE 17–1
DXA Values in Patients Undergoing Natural Menopause (P = .001)
Spinal fractures (n = 81) No spinal fractures (n = 225)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
0.80 (0.14 g/cm2) 0.89 (0.16 g/cm2)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abbreviation: DXA, dual-energy x-ray absorptiometry.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures TABLE 17–2
429
Spinal Fracture Prevalence in Postmenopausal Women as Related to DXA
DXA (g/cm2) 0.8–0.9 0.7–0.8 0.6–0.7 0.5–0.6 % With Spinal Fractures 26 33 51 63
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abbreviation: DXA, dual-energy x-ray absorptiometry.
bone.48 Fracture healing traditionally proceeds through the six stages of endochondral bone formation: impact, induction, inflammation, soft tissue callus (chondroid), hard tissue callus (osteoblastic), and remodeling.62 Although the stages from fracture through chondrogenesis are unaltered, the final two stages, hard callus and remodeling, are clearly susceptible to alteration in osteoporotic patients.84 The synthesis of bone and its mineralization depend on the calcium environment. Osteoporotic patients have a diminished pool of rapidly soluble calcium, inadequate dietary calcium, and a deficient structural calcium bone reserve.61 Calcium mineralization is subject to delay, and the stage of remodeling is prolonged because of competition for ionized calcium with the rest of the body. Also, substances that may have been mobilized to maintain systemic calcium homeostasis (PTH and vitamin D) may compromise the latter stages of fracture repair. In addition, up to 40% of elderly patients are mildly to moderately malnourished, and this condition compromises bone collagen synthesis.81 Bone scans remain positive (indicating continued metabolic remodeling) well into the third year after fracture in elderly persons, and union cannot be fully ascertained until that time.25 Studies have demonstrated that osteoporotic rats have delayed healing. It is uncertain whether it is the osteoporosis or the estrogen deficiency that compromises fracture repair.72, 106 Systemic bone loss occurs in the unaffected skeleton after long bone fractures, even when the patient has adequate calcium intake.103 Osteoporotic patients, who are typically chronically calcium deficient, may be more affected. Ideally, healing could be stimulated in such patients by physiologic levels of vitamin D (400 to 800 IU/day) and calcium (1500 mg of elemental calcium per day), normal nitrogen balance, and appropriate exercise.79
DEFINITION AND DIAGNOSIS
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is defined as a disease of decreased bone mass and changes in the microarchitecture of the skeleton. The disease may be recognized clinically in one of three ways: acute fracture (most commonly of the wrist, ribs, hip, or spine), asymptomatic thoracic wedge or lumbar compression fracture, or generalized osteopenia on a radiograph. More than 65% of individuals presenting with compression fractures are asymptomatic.35 Critical determinations are the cause and the extent of bone loss. A
diagnosis of osteopenia must differentiate among bone marrow disorders, endocrinopathy, osteomalacia, and osteoporosis.5, 79 The workup for osteopenia involves invasive and noninvasive methods. Operational definitions of osteopenia and osteoporosis are based on bone mass and density. Noninvasive techniques of determining osteopenia are used to quantitate bone mass and evaluate the efficacy of treatment. The simple radiograph is fraught with technical difficulty and may not identify osteopenia until 30% of the bone mass has been lost.49 Current methodology centers on dualphoton absorptiometry, quantitative computed tomography (CT), and ultrasonography. Dual-energy x-ray absorptiometry (DEXA) utilizes two energy levels.33, 58, 98 It permits correction for soft tissue and allows direct measurement of total bone mass (cortical and trabecular) within a specified amount of mineralized tissue of an aerial section of the spine or hip; the measurements are analyzed and expressed as grams per centimeter squared. Radiation is low (5 mrad) and precision (1% in the spine, 3% to 4% in the hip) and accuracy (4% to 6%) are good. Compression fractures, osteophytes, degenerative changes, and vascular calcifications can elevate local readings. A lumbar lateral radiograph is needed to correct for these artifacts. After the density has been calculated, comparisons can be made with age-matched peers (Z score) and with an adult population with peak bone mass (T score). A bone mass within 1 standard deviation is considered healthy. Osteopenia is defined between 1 and 2.4 standard deviations below peak bone mass. A bone mass 2.5 standard deviations below peak mass is considered frank osteoporosis. Individuals with a bone mass more than 1.5 standard deviations below that of their peers probably have a secondary cause of osteoporosis that must be evaluated. Alternative methods are also used to determine bone mass. CT is used to measure the midportion of the vertebral body and determine trabecular bone mass against a simultaneous phantom; in this way, it can be used to measure trabecular bone mass directly. It uses 20 times as much radiation and has poorer precision than DEXA.34 Ultrasonography is used to examine the heel, patella, tibia, and peripheral sites and measure several properties of bone; these measurements have a correlation of 0.75 with central density readings.100 As discussed previously, these noninvasive methods cannot clearly identify absolute fracture risk, but they can be used as a loose guide for management grouping and as an exacting tool for long-term determination of treatment efficacy. There are also markers of skeletal metabolic activity. Bone formation markers are bone-specific alkaline phosphatase and osteocalcin. Alkaline phosphatase rises within 5 days after a fracture is sustained. If the level is elevated at the time of fracture, it is due to a high-turnover state until proved otherwise. Hyperparathyroidism and osteomalacia must be considered in the workup. Bone collagen breakdown products can be used to measure bone turnover. Collagen molecules in the bone matrix are staggered to form fibrils that are joined by covalent crosslinks consisting of hydroxylysyl-pyridinoline (pyridinoline, Pyd) and lysyl-pyridinoline (deoxypyridinoline, Dpd). Dpd has greater specificity because Pyd is present in other connective tissues. Dpd and Pyd are linked to
Copyright © 2003 Elsevier Science (USA). All rights reserved.
430
SECTION I • General Principles
collagen where two aminotelopeptides (N-telopeptides [NTX] and C-telopeptides) are linked to a helical site and are released with Dpd and Pyd during osteoclastic bone resorption. These products are released into the circulation, metabolized by the liver and kidney, and excreted in the urine. Clinical applications of these markers include monitoring effectiveness of therapy,32 prediction of fracture risk,31 and selection of patients for antiresorptive therapy.12 NTX and DEXA provide highly sensitive, commonly used indices of metabolic activity and bone mass in clinical practice.73 High-turnover states such as hyperparathyroidism are characterized by high NTX levels. Osteoporosis (as determined by DEXA) has been divided into high turnover (high NTX) related to increased osteoclast activity and low turnover (low NTX) related to low osteoclast activity.73 No signs, symptoms, or diagnostic tests are specific for osteoporosis. In one study, 31% of osteoporotic women were found to have disorders with possible effects on skeletal health without major risk factors for postmenopausal osteoporosis.13 An algorithm for the diagnosis of osteopenia has been developed (Table 17–3). When osteopenia has been defined and localized bone disorders have been eliminated, the differential workup commences. First, a hematologic profile, serum protein electrophoresis, and biochemical profile studies are obtained. In common bone marrow disorders, including leukemia and myeloma (which together account for 1% to 2% of cases of osteoporosis), the bone marrow screen is usually abnormal (anemia, low white blood cell count, or low platelet count). A biochemical panel provides information on renal and hepatic function, primary hyperparathyroidism (high serum calcium), and possible malnutrition (anemia, low calcium, low phosphorus, or low albumin). If the bone marrow screen is negative, the diagnostic testing then centers on endocrinopathies. Premature menopause, iatrogenic Cushing’s disease, and type I diabetes mellitus are diagnosed by history. Determinations of PTH and thyroid-stimulating hormone identify hyperparathyroidism and hyperthyroidism. The latter may occur as osteoporosis and severe weight loss or as iatrogenic
hyperthyroidism, caused by overuse of thyroid replacement hormone medication by obese patients to control weight.80 Malnutrition is common in osteoporotic patients. Osteomalacia occurs in 8% of osteopenic patients in northern areas and may be identified by low levels of 25-hydroxyvitamin D, high secondary PTH, high alkaline phosphatase, low urinary calcium, low serum phosphorus, and low to normal serum calcium values. The mild hyperosteoidosis and lag in mineralization are often indistinguishable from those seen in osteoporosis by laboratory studies. The critical diagnostic study used to differentiate osteomalacia from osteoporosis is the transileal bone biopsy and histomorphometric analysis of the undecalcified bone.65 These studies permit a definitive diagnosis. If cost containment were not an issue, bone densitometry would be readily available to almost all postmenopausal women. Medicare now covers DEXA for estrogendeficient women older than 65 years. A cost-effectiveness analysis supported by the National Osteoporosis Foundation concluded that it is worthwhile to measure bone density in any woman with a vertebral fracture and in all white women older than 60 to 65 years. In healthy postmenopausal women between 50 and 60 years old, indications for DEXA include a history of low-trauma fracture, weight under 127 pounds, smoking, or a family history of an osteoporotic fracture.24 Most experts also agree that any patients with secondary causes of known bone loss should have their bone density measured.
MEDICAL TREATMENT AND PREVENTION
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Osteoporosis is a heterogeneous disease of multifactorial causes. The principles of medical management necessitate decisions about whether bone mass should be maintained or augmented. If the patient has crossed his or her fracture threshold, bone augmentation is required. However, if the
TABLE 17–3
Sequence for the Workup of the Most Common Forms of Osteomalacia
Complete blood count Erythrocyte sedimentation rate Serum protein electrophoresis Parathyroid hormone Thyroid-stimulating hormone History of type I diabetes History of steroid use Normal ↓ Calcium (serum-urine) Phosphorus (serum) Alkaline phosphatase Blood urea nitrogen 25-Hydroxyvitamin D Parathyroid hormone Transileal bone biopsy (?)
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Abnormal 1%–2% ↓ Normal Abnormal 15%–25% ↓ Normal
→
Bone marrow biopsy
Myeloma Leukemia Benign marrow disorder Hyperparathyroidism Hyperthyroidism Diabetes mellitus (type I) Cushing’s disease
→
Abnormal 8% ↓ Normal Osteoporosis
→
Osteomalacia
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures
431
trauma level was of sufficient magnitude, maintenance may be all that is needed, even after a fracture. A careful history of the cause of the fracture and a noninvasive measurement of bone mass are essential. Adequate levels of exercise,1, 21, 46, 59, 84 calcium,36, 40 and vitamin D (400 to 800 IU/day) maintain both cortical and trabecular bone mass except in the early postmenopausal spine, when the loss is 2% per year. Physiologic levels of calcium intake, as determined by a National Institutes of Health consensus conference in 1994, are 1200 to 1500 mg/day from age 12 to 24 years, 1000 mg/day from age 25 years until menopause, and 1500 mg/day after menopause.83 Currently, bisphosphonates (alendronate and risedronate), raloxifene, and calcitonin are approved for treatment and low-dose alendronate and raloxifene are approved for prevention of osteoporosis. The Food and Drug Administration has approved estrogen for prevention and management of osteoporosis. Only alendronate has been labeled specifically for men, and bisphosphonates have not been approved for premenopausal women, particularly because of pregnancy. A treatment program has been approved by the National Osteoporosis Foundation for patients at risk of fragility fracture.84 Treatment is recommended for any individual with a T score of −2.5 or a score of −1.5 with four major risk factors, and prevention is recommended for a patient with osteopenia. If an individual has a known vertebral fracture, the use of hormone replacement therapy, alendronate, or calcitonin is recommended. For a patient without fracture and unwilling to consider treatment, physiologic calcium levels, vitamin D (400 to 800 units per day), exercise, and smoking cessation are recommended. Calcium, smoking cessation, and exercise are recommended for postmenopausal patients younger than 65 years without risk factors. These recommendations were made with Food and Drug Administration approval of estrogen for the treatment of osteoporosis; new treatment guidelines need to be established because the new labeled use of estrogen is for the prevention and management of osteoporosis.
is indicated only for prevention and management of osteoporosis, because long-term randomized control studies have not been performed to determine whether estrogen is an effective long-term fracture prevention treatment for osteoporosis.
Raloxifene
A series of synthetic estrogen-like modulators have been developed. These agents can compete with estrogen binding sites and seem to function more like an estrogen at bone and work effectively as antiresorptive agents. They are indicated for prevention of osteoporosis and treatment of vertebral fractures. Tamoxifen was used as an antiestrogen, particularly for patients with breast cancer. Bone cells are also responsive to tamoxifen.88 Individuals taking tamoxifen have 70% of the benefit of estrogen in terms of maintaining bone mass.15 It is not used as an antiosteoporotic agent because 70% of women have significant postmenopausal symptoms and a high incidence of uterine cancer. Raloxifene, a newer agent, is not associated with an increased incidence of uterine cancer, and early data suggest that there is a decreased risk of breast cancer in patients using raloxifene compared with control subjects.22 A trial comparing tamoxifen and raloxifene in preventive action against breast cancer is under way.18 Raloxifene is approved for the prevention of osteoporosis. Raloxifene can decrease the risk of vertebral fracture by approximately 40% to 50%, but there is no reported protection for the hip.28 Adverse effects include an 8% incidence of leg cramps and an increased risk of thrombophlebitis comparable with that associated with estrogen. It is not recommended in the first 5 years of menopause because it enhances postmenopausal symptoms.
Estrogen
Estrogen* has been the most studied and used drug for the prevention of osteoporosis. Epidemiologic studies, cohort and case-control, indicated that estrogen administration to postmenopausal women decreased skeletal turnover (25% to 50%) and the rate of bone loss in women 6 months to 3 years after menopause.12, 74 A large, longitudinal cohort study of 9704 postmenopausal women 65 years of age and older found that estrogen use was associated with a significant decrease in wrist fracture (relative risk [RR], 0.39) and of all nonspinal fractures (RR, 0.66). It appears to reduce risk of hip fractures by 20% to 60%.9 To prevent up to a ninefold increase in the probability of uterine cancer with estrogen alone, estrogen should be cycled with progesterone. Estrogen may not provide cardiac protection, and it increases the risk for breast cancer (by as much as 30%).2, 6, 42, 86 Currently, estrogen
*See references 6, 10, 28, 29, 44, 45, 57, 70, 71, 104, 105.
Calcitonin
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid. It may play a role in the skeletal development of the embryo and fetus, but its primary action is on bone to reduce osteoclastic bone resorption by diminution of osteoclasts (shrinkage of cells, loss of ruffled border, reduction in resorptive activity, and increased apoptosis).11 It has been effectively used in patients with hypercalcemia, Paget’s disease, and osteoporosis. It is indicated for the treatment of postmenopausal women more than 5 years after menopause with low bone mass compared with healthy premenopausal women. A nasal form of calcitonin at a dosage of 200 units per day appears to increase bone mass in the spine and decrease spinal fractures by 37%. To date, there has been no benefit in hip fracture prevention.8, 85 Calcitonin does have another benefit of providing some analgesia. It has been used in patients with painful osteoporotic fractures and does not interfere with fracture healing.89 The only established side effect is rhinitis (23% versus 7% for placebo).26
Copyright © 2003 Elsevier Science (USA). All rights reserved.
432
SECTION I • General Principles
Bisphosphonates
Bisphosphonates are stable, active analgesics of pyrophosphate68 that inhibit osteoclastic resorption and depress bone turnover27, 49, 58, 87 by binding to the osteoclastresorbing surface and acting as a nondegradable shield. When absorbed by the osteoclast, they inhibit osteoclast function. Bisphosphonates have low bioavailability, and less than 1% is absorbed orally. Alendronate is the first bisphosphonate approved for the treatment of osteoporosis. Low-dose alendronate, 5 mg/day or 10 mg three times a week, is approved for prevention of osteoporosis. It has been shown to increase bone mass in the hip and spine. It decreased the risk of all fractures by approximately 50% after 1 year of treatment.7, 17, 67 Regardless of the degree of bone mass enhancement, all patients treated with alendronate had equal protection against fractures, suggesting an improvement in bone quality. Alendronate has been associated with esophageal irritation, and as many as 30% of individuals have had esophagitis; in a carefully controlled study, the rate of esophagitis was comparable to that in the placebo group.67 Currently, a once-weekly dosage of 70 mg is as efficacious and produces significantly less indigestion. Risedronate, at 5 mg/day, is the second bisphosphonate approved for both prevention and treatment of osteoporosis. It has a profile similar to that of alendronate and may cause less esophageal irritation. It reduced the risk of new vertebral fractures by 49% over 3 years compared with a control group (P < .001), and the risk of nonvertebral fractures was reduced by 33% compared with a control group over 3 years (P = .06).96 Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of the placebo group.95 A head-to-head comparison of the two agents has not been performed. Bisphosphonates have a long-lasting effect on bone. A double-blind, multicenter study of postmenopausal women101 (at least 2.5 standard deviations below the peak premenopausal mean) compared the efficacy and safety of treatment with oral once-weekly alendronate at 70 mg (n = 519), twice-weekly alendronate at 35 mg (n = 369), and daily alendronate at 10 mg (n = 370) for 1 year. Increases in bone density of the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly showed reduced biochemical markers of bone resorption (urinary Ntelopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) in the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal adverse experiences. There were fewer serious upper gastrointestinal adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared with the daily dosing group. This study suggests that once-weekly dosing of bisphosphonates may provide a more convenient, therapeutically equivalent alternative to daily dosing. Pamidronate has not been approved for treating osteoporosis but is used for treating patients with metastatic disease, hypercalcemic malignancy, and Paget’s
disease. At our institution, The Hospital for Special Surgery in New York, intravenous doses of pamidronate have been successful in treating osteoporosis in this population. A combination regimen of alendronate and estrogen has been studied. A randomized controlled trial indicated that a combination of alendronate and estrogen was superior to the single agents in terms of bone density augmentation.69
MANAGEMENT OF OSTEOPOROTIC FRACTURES
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz The impact of skeletal loss becomes most apparent as the skeleton begins to fail in its ability to withstand normal loads. When the skeleton no longer functions structurally, osteoporosis becomes a disease state. The overriding goal of management of fractures in the osteoporotic patient is to achieve early and definitive stabilization of the injured extremity. At The Hospital for Special Surgery in New York, an osteoporosis treatment center has been established. The experiences derived from management in a large combined population have given rise to the following treatment principles and protocols: 1. Elderly patients are best served by rapid, definitive fracture care that allows early mobilization. In the patient with concurrent illnesses or markedly abnormal laboratory results, medical evaluation and stabilization of reversible medical decompensations should be performed before surgery.35 In most cases, patients are at their respective homeostatic optimum on the day of injury and should ideally be treated with surgery at that time. 2. Surgical treatment is directed at achieving stable fracture fixation and early return of function. In the lower extremity, this implies early weight bearing. Anatomic restoration is important in intra-articular fractures, whereas stability is the goal in the treatment of metaphyseal and diaphyseal fractures. 3. Surgical procedures are designed with an effort to minimize operative time, blood loss, and physiologic stress. 4. Osteoporotic bone, with its decreased density, lacks the strength to hold screws and plates securely and more often involves comminution.8 As a result, failure of internal fixation is caused primarily by bone failure rather than by implant failure. Internal fixation devices are chosen that allow impaction of the fracture fragments into stable patterns that minimize the load carried by the implants. In addition, implants that minimize stress shielding are chosen to prevent further skeletal decompensation of the involved bone. For these reasons, sliding nail plate devices and intramedullary devices that are load sharing and allow fracture compression are the devices of choice. 5. Because most of these fractures are related to underlying metabolic bone disease, a full evaluation of the etiologic condition is performed and an appropriate
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures
433
medical therapeutic program is developed for each patient. 6. An inadequate calcium intake could result in deficits in callus mineralization or remodeling.25 Because many elderly patients are malnourished, nutritional assessment should be included in the patient’s evaluation. The specific management of fractures about the knee and of Colles’, hip, spine, proximal humeral, and pelvic fractures is discussed elsewhere in appropriate chapters. This chapter includes a discussion of the femoral neck fracture because of its strong implications for metabolic bone disease. A series of studies from the fracture service at New York Hospital99 demonstrated that 8% of patients with femoral neck fracture had frank osteomalacia. Although 40% had marked trabecular bone loss (less than 15% trabecular bone volume, with normal being more than 22%), all patients older than 50 years had some reduction of bone mass when compared with younger persons. Twenty-five percent had increased metabolic turnover indices, including a high osteoclast count. In the series of Scileppi and colleagues,101 bone histomorphometry appeared to be a good predictor of outcome after treatment for femoral neck fracture.61 Patients who had trabecular bone volume that was within 60% of normal (i.e., volume higher than 15%) had an 85% to 95% rate of successful union, whereas for patients who had severe trabecular bone loss (to less than 15% of bone volume) the rate was lower than 33% in women and lower than 50% in men. These combined studies at New York Hospital suggest that significant metabolic bone disease, particularly osteoporosis, leads to a high rate of unsuccessful union after femoral neck fracture. Comparable studies of other fractures commonly associated with osteoporosis are lacking, but presumably osteoporosis per se affects the type, severity, and repair process in these fractures as well. Application of the outcome studies of femoral neck fractures in relation to osteopenia has resulted in specific protocols at The Hospital for Special Surgery and the New York Presbyterian Hospital. Our current protocol for treatment of a displaced femoral neck fracture in the ambulatory patient who is physiologically younger than 65 years relies on closed reduction and stable internal fixation using the sliding compression screw or cannulated screws as the primary form of treatment. If stability cannot be achieved, the patient is treated with a hemiarthroplasty. The ambulatory patient who is physiologically older than 70 years is treated by hemiarthroplasty. Closed reduction and pinning are the method of choice in caring for the nonambulatory patient. Patients with severe demineralizing bone disease (marked osteoporosis), pathologic fractures secondary to metastasis, or neurologic disorders that require immediate ambulation and patients who cannot comply with physical therapy regimens requiring partial weight bearing are treated with primary hemiarthroplasty. Traditionally, treatment of vertebral compression fractures consists of medical pain management. In 1984, vertebroplasty, structural reinforcement of the vertebral body with polymethylmethacrylate cement, was first used in the treatment of osteoporotic vertebral fractures. The primary indication for vertebroplasty is pain relief. The procedure is performed under local or general anesthesia
and a transpedicle or extrapedicle approach is used to reach the anteroinferior border of the vertebral body. In vertebroplasty, radiodense polymethylmethacrylate cement is injected into the vertebral body under high pressure using Luer-Lok syringes in 2- to 3-ml allotments. Several cohort studies reported a decrease in pain in 80% to 90% of patients, a complication rate of 5% to 6%, and no fracture reduction.4, 23, 47 Kyphoplasty is a similar procedure designed to provide significant pain relief, rapid return to activities of daily living, restoration of vertebral body height, and reduction in spinal deformity. In this procedure, a balloon tamp is inserted into the center of the collapsed vertebral body and inflated with radiopaque liquid under fluoroscopic guidance. The patient is continually monitored by sensory evoked potential for neural damage throughout the procedure at The Hospital for Special Surgery. The balloon strikes cancellous bone circumferentially around the tamp and thereby reduces the deformation and restores height to the vertebral body. The balloon is deflated and removed, and the cavity is filled with the surgeon’s choice of biomaterial, stabilizing the fracture. Approximately 1000 fractures in 600 patients have been treated by this technique. A review of 226 kyphoplasties in 121 patients63 found that 96% of patients had pain relief as determined using a pain analogue scale. There was 45% restoration of height in the anterior plane, 71% at the midline, and 54% posteriorly. In this series, there was one case of epidural bleeding requiring decompression, one incomplete spinal injury, and one report of transient adult respiratory distress syndrome. No episodes of infection, pulmonary emboli, or myocardial infarction have been reported. In this study, the average age was 73.7 years and each patient had on average 3.7 co-morbidities. A quality-of-life questionnaire (called SF-36) was administered to patients before and after kyphoplasty.69a The questionnaire is standardized and validated and is designed to assess functional status and well-being. The questions are used to calculate summary measures of physical and mental health such as bodily pain and physical function. The summary measures are then normalized to a scale of 1 to 100, where 1 is the lowest score and 100 is the highest or best score. In these patients, both bodily pain and physical function scores improved significantly (P < .004 for bodily pain, P < .02 for physical function) when assessed 1 week after kyphoplasty. These preliminary data suggest that kyphoplasty is an effective, minimally invasive technique for providing pain relief and restoration of vertebral height.
REFERENCES 1. Aloia, J.E.; Cohn, S.H.; Ostuni, J.A.; et al. Prevention of involutional bone loss by exercise. Ann Intern Med 89:356, 1978. 2. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med 117:1038, 1992. 3. Avioli, L.V. Postmenopausal osteoporosis: Prevention vs. cure. Fed Proc 40:2418, 1981. 4. Barr, J.D.; Barr, M.S.; Lemley, T.J.; McCann, R.M. Percutaneous vertebroplasty for pain relief and spinal stabilization. Spine 25:923, 2000.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
434
SECTION I • General Principles 30. Frost, H.M. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res 3:211, 1969. 31. Garnero, P.; Hausherr, E.; Chapuy, M.C.; et al. Markers of bone resorption predict hip fracture in elderly women: The EPIDOS prospective study. J Bone Miner Res 11:1531, 1996. 32. Garnero, P.; Shih, W.J.; Gineyts, E.; et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693, 1994. 33. Genant, H.K.; Boyd, D.P. Quantitative bone mineral analysis using dual energy computed tomography. Invest Radiol 12:545, 1977. 34. Glaser, D.L.; Kaplan, F Osteoporosis: Definition and clinical .S. presentation. Spine 22(Suppl 24):12S, 1997. 35. Glimcher, M.A. On the form and structure of bone from molecules to organs: Wolff’s law revisited. In: Veis, A., ed. The Chemistry and Biology of Mineralized Tissues. New York, Elsevier–North Holland, 1982, p. 613. 36. Greenspan, S.L.; Myers, E.R.; Maitland, L.A.; et al. Fall severity and mineral density as risk factors for hip fracture in ambulatory elderly. JAMA 271:128, 1994. 37. Hakkinen, K. Force production characteristics of leg extensor, trunk flexor, and extensor muscles in male and female basketball players. J Sports Med Phys Fitness 31:325, 1991. 38. Hansen, M.A.; Overgaard, K.; Riss, B.J.; Christiansen, C. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 303:1548, 1991. 39. Hayes, W.C.; Myers, E.R.; Morris, J.N.; et al. Impact near the hip dominates fracture risk in elderly nursing home residents who fall. Calcif Tissue Int 52:192, 1993. 40. Heaney, R.P. Effect of calcium on skeletal development, bone loss, and risk of fractures. Am J Med 91:23S, 1991. 41. Heaney, R.P. Nutrition and Osteoporosis. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 270. 42. Hemminki, E.; Topo, P.; Malin, M.; Kangas, I. Physician’s views on hormone therapy around and after menopause. Maturitas 16:163, 1993. 43. Holbrook, T.; Grazier, K.; Kelsey, J.; et al. The frequency of occurrence, impact and cost of selected musculoskeletal conditions in the United States. Chicago, Ill.: American Academy of Orthopedic Surgeons, 1984. 44. Horseman, A.; Gallagher, J.C.; Simpson, M.; et al. Prospective trial of oestrogen and calcium in postmenopausal women. BMJ 2:789, 1977. 45. Hutchinson, T.A.; Polansky, S.M.; Feinstein, A.R. Postmenopausal oestrogens protect against fractures of hip and distal radius: A case control study. Lancet 2:705, 1979. 46. Jacobsen, P.C.; Beaver, W.; Grubb, S.A.; et al. Bone density in women; college athletes and older athletic women. J Orthop Res 2:328, 1984. 47. Jansen, M.E.; Evans, A.J.; Mathis, J.M.; et al: Percutaneous polymethylmethacrylate vertebroplasty in the treatment of osteoporotic vertebral body compression fractures: Technical aspects. AJNR 18:1897, 1997. 48. Johnson, T.R.; Tomin, E.; Lane, J.M. Perspectives on growth factors, bone graft substitutes and fracture healing. In: Obrant, K., ed. Management of Fractures in Severely Osteoporotic Bone. London, Springer, 2000, p. 111. 49. Johnston, C.C., Jr.; Epstein, S. Clinical, biochemical, epidemiologic, and economic features of osteoporosis. Orthop Clin North Am 12:559, 1981. 50. Jones, B.H.; Bovee, M.W.; Harris, J.M.; et al: Intrinsic risk factors for exercise-related injuries among male and female army trainees. Am J Sports Med 21:705, 1993 51. Jones, B.H.; Cowan, D.N.; Tomlinson, J.P.; et al: Epidemiology of injuries associated with physical training among young men in the army. Med Sci Sports Exerc 25:197, 1993. 52. Jowsey, J. Bone morphology: Bone structure. In: Sledge, C.B., ed. Metabolic Disease of Bone. Philadelphia, W.B. Saunders, 1977, pp. 41–47. 53. Juppner, H.; Brown, E.M.; Kronenberg, H.M. Parathyroid hormone. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 80.
5. Barth, R.W.; Lane, J.M. Osteoporosis. Orthop Clin North Am 19:845, 1988. 6. Belchetz, P.E. Hormonal treatment of postmenopausal women. N Engl J Med 330:1062, 1994. 7. Black, D.M.; Cummings, S.R.; Karph, D.B.; et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535, 1996. 8. Cardona, J.M.; Pastor, E. Calcitonin versus etidronate for the treatment of postmenopausal osteoporosis: A meta-analysis of published clinical trials. Osteoporos Int 7:165, 1997. 9. Carter, D.R.; Hayes, W.C. The compressive behavior of bone as a two-phase porous structure. J Bone Joint Surg Am 59:954, 1977. 10. Cauley, J.A.; Seeley, D.G.; Ensrud, K.; et al. Estrogen replacement therapy and fractures in older women: Study of Osteoporosis Research Group. Ann Intern Med 122:9, 1995. 11. Chambers, T.J.; Moore, A. The sensitivity of isolated osteoclasts to morphological transformation by calcitonin. J Clin Endocrinol Metab 57:819, 1983. 12. Chesnut, C.H., III; Bell, N.H.; Clark, G.S.; et al. Hormone replacement therapy in postmenopausal women: Urinary Ntelopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med 102:29, 1997. 13. Clark, J.; Tamenbaum, C.; Posnett, K.; et al. Laboratory testing in healthy, osteopenic women. J Bone Miner Res 12:S141, 1997. 14. Compston, J.E. Connectivity of cancellous bone: Assessment and mechanical implications. Bone 15:63, 1994. 15. Cosman, F Lindsay, R. Selective estrogen receptor modulators: .; Clinical spectrum. Endocr Rev 20:418, 1999. 16. Courtney, A.C.; Washtel, E.F Myers, E.R.; Hayes, W.C. Age-related .; reductions in the strength of the femur tested in a fall-loading configuration. J Bone Joint Surg Am 77:387, 1995. 17. Cummings, S.R.; Black, D.M.; Thompson, D.E.; et al. Effect of alendronate on risk of fracture in women with low bone density by without vertebral fractures. JAMA 280:2077, 1998. 18. Cummings, S.R.; Eckert, S.; Kreuger, K.A.; et al. The effects of raloxifene on the risk of breast cancer in postmenopausal women: Results from the MORE (Multiple Outcome of Raloxifene Evaluation) randomized trial. JAMA 281:2189, 1999. 19. Cummings, S.R.; Kellsey, J.L.; Nevitt, M.C.; O’Dowd, K.J. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178, 1985. 20. Cummings, S.R.; Nevitt, M.C.; Browner, W.S.; et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767, 1995. 21. Dalsky, G.P.; Stocke, K.S.; Ehsani, A.A.; et al. Weight-bearing exercise training and lumbar bone mineral content in postmenopausal women. Ann Intern Med 108:824, 1988. 22. Delmas, P.D.; Bjarnason, N.H.; Mitlak, B.H.; et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641, 1997. 23. Deramond, H.; Darrason, R.; Galibart, P. Percutaneous vertebroplasty with acrylic cement in the treatment of aggressive spinal angiomas. Rachis 1:143, 1989. 24. Eddy, D.M.; Cummings, S.R.; Johnson, C.C.; et al. Osteoporosis: Review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis. Osteoporos Int 8:S1, 1998. 25. Einhorn, T.A.; Bonnarens, F Burstein, A.H. The contributions of .; dietary protein and mineral to the healing of experimental fractures: A biomechanical study. J Bone Joint Surg Am 68:1389, 1986. 26. Ellerington, M.C.; Hillard, T.C.; Whitcroft, S.I.J.; et al. Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis. Calcif Tissue Int 59:6, 1996. 27. Endo, Y.; Nakamora, M.; Kikuchi, T.; et al. Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo. Calcif Tissue Int 52:248, 1993. 28. Ettinger, B; Black, D.M.; Mitlak, B.H.; et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a three year randomized clinical trial. JAMA 282:637, 1999. 29. Ettinger, B.; Genant, H.K.; Cann, C.E. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 102:319, 1985.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
CHAPTER 17 • Osteoporotic Fragility Fractures 54. Kelsey, J.F Osteoporosis: Prevalence and incidence. In: Proceedings . of the NIH Consensus Development Conference, April 22, 1984. Bethesda, MD, National Institutes of Health, 1984, p. 25. 55. Kempson, G. The mechanical properties of articular cartilage and bone. In: Owen, R.; Goodfellow, J.; Bullough, P., eds. Scientific Foundations of Orthopaedics and Traumatology. Philadelphia, W.B. Saunders, 1980, p. 49. 56. Kenzora, J.E.; McCarthy, R.E.; Lowell, J.D.; Sledge, C.C. Hip fracture mortality: Relation to age, treatment, preoperative illness, time of surgery, and complications. Clin Orthop 186:45, 1985. 57. Kiel, D.P.; Felson, D.T.; Anderson, J.J.; et al. Hip fracture and the use of estrogens in postmenopausal women. N Engl J Med 317:1169, 1987. 58. Kimmel, P.L. Radiologic methods to evaluate bone mineral content. Ann Intern Med 100:908, 1984. 59. Krolner, B.; Toft, B.; Pors Nielsen, S.; et al. Physical exercise as a prophylaxis against involutional vertebral bone loss: A controlled trial. Clin Sci (Colch) 64:541, 1983. 60. Lane, J.M.; Vigorita, V.J. Osteoporosis. Orthop J 1:22, 1985. 61. Lane, J.M.; Cornell, C.N.; Healey, J.H. Orthopaedic consequences of osteoporosis. In: Riggs, B.L.; Melton, L.J., III, eds. Osteoporosis: Etiology, Diagnosis and Management. New York, Raven Press, 1988, p. 111. 62. Lane, J.M.; Werntz, J.R. Biology of fracture healing. In: Lane, J., ed. Fracture Healing. New York, Churchill Livingstone, 1987, p. 49. 63. Lane, J. M.; Girardi, F Parvataneni, H.; et al. Preliminary outcomes .; of the first 226 consecutive kyphoplasties for the fixation of painful osteoporotic vertebral compression fractures. Paper presented at the World Congress on Osteoporosis 2000, June 2000. 64. Lane, J.M. Metabolic bone disease and fracture healing. In: Heppenstall, R.B., ed. Fracture Treatment and Healing. Philadelphia, W.B. Saunders, 1980, p. 946. 65. Lane, J.M.; Vigorita, V.J.; Falls, M. Osteoporosis: Current diagnosis and treatment. Geriatrics 39:40, 1984. 66. Lane, J.M.; Healey, J.H.; Schwartz, E.; et al. The treatment of osteoporosis with sodium fluoride and calcium: Effects on vertebral fracture incidence and bone histomorphometry. Orthop Clin North Am 15:729, 1984. 67. Lane, J.M.; Russell, L.; Khan, S.N. Osteoporosis. Clin Orthop 372:139, 1999. 68. Leiberman U.A.; Weiss S.R.; Broll J.; et al. Effect of oral alendronate on bone mineral density and the incidence of fracture in postmenopausal osteoporotic women. N Engl J Med 333:1437, 1995. 69. Lian, J.B.; Stein, G.S.; Canalis E.; et al. Bone formation: Osteoblast lineage cells, growth factors, matrix proteins, and the mineralization process. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 14. 69a. Lieberman, I.; Dudeney, S.; Reinhardt, M-K.; Bell, G. Initial outcome and efficacy of kyphoplasty in the treatment of painful osteoporosis vertebral compression fractures. Spine 26:1631, 2001. 70. Lindsey, R.; Bush, T.L.; Lobo, R.A.; et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis. A randomized controlled trial. J Clin Endocrinol Metab 84:3078, 1999. 71. Lindsey, R.; Hart, D.M.; Aitken, J.M.; et al. Long-term prevention of postmenopausal osteoporosis by estrogen. Lancet 1:1038, 1976. 72. Lindsey, R.; Hart, D.M.; Aitken, J.M.; et al. Prevention of spinal osteoporosis in oophorectomised women. Lancet 2:1151, 1980. 73. Lindsey, R.; Hart, D.M.; MacLean, A. Bone response to termination of oestrogen treatment. Lancet 1:1325, 1978. 74. Loucks, A.B.; Motorola, J.F Girton, L.; et al: Alterations in the .; hypothalamic-pituitary-ovarian and the hypothalamic-pituitaryadrenal axis in the athletic woman. J Clin Endocrinol Metab 68:402, 1989. 75. Lufkin, E.G.; Wahner, H.W.; O’Fallon, W.M.; et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 117:1, 1992. 76. Melton, L.J., III; Riggs, B.L. Epidemiology of age-related fractures. In: Avioli, L.V., ed. The Osteoporotic Syndrome: Detection, Prevention and Treatment. Orlando, FL, Grune & Stratton, 1983, p. 45. 77. Melton, L.J., III; Riggs, B.L. Epidemiology of age-related fractures. In: Avioli, L.V., ed. The Osteoporotic Syndrome. New York, Grune & Stratton, 1987, pp. 1–30.
435
78. Melton, L.J.I.; Khosla, S.; Atkinson, E.J.; et al. Relationship of bone turnover to bone density and fractures. J Bone Miner Res 12:1083, 1997. 79. Meunier, P.J. Prevention of hip fractures. Am J Med 95:755, 1993. 80. Mohler, D.G.; Lane, J.M.; Cole, B.J.; Winerman, S.A. Skeletal fracture in osteoporosis. In: Lane, J.M.; Healey, J.H., eds. Diagnosis and Management of Pathological Fractures. New York, Raven Press, 1993, p. 13. 81. Mosekilde, L.; Eriksen, E.F Charles, P. Effects of thyroid hormone .; on bone and mineral metabolism. Endocrinol Med Clin North Am 19:35, 1990. 82. Mullen, J.O.; Mullen, N.L. Hip fracture mortality: A prospective multifactorial study to predict and minimize death risk. Clin Orthop 280:214, 1992. 83. National Institutes of Health Consensus Development Conference Statement on Osteoporosis, Vol. 5, No. 3, 1984. JAMA 252:799, 1985. 84. NIH Consensus Conference. Optimal calcium intake. JAMA 272:1942, 1994. 85. National Osteoporosis Foundation. Osteoporosis: Review of the evidence for the prevention, diagnosis, and treatment and costeffectiveness analysis. Osteoporos Int 8:1, 1998. 86. Ott, S.M. Clinical effects of bisphosphonates in involutional osteoporosis. J Bone Miner Res 8(Suppl):597, 1993. 87. Overgaard, K.; Hansen, N.A.; Jensen, S.B.; et al. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis. A dose response study. Bone Miner 305:556, 1992. 88. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of estrogen on estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 273:199, 1995. 89. Powels, T.J.; Hicklish, T.; Kanis, J.A.; et al. Effect of tamoxifen on bone mineral density measured by dual energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 18:78, 1995. 90. Pun, K.K.; Chan, L.W. Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures. Clin Endocrinol (Oxf) 30:435, 1989. 91. Ray, N.F Chan, J.K.; Thamer, M.; et al. Medical expenditures for .; the treatment of osteoporotic fractures in the United States in 1995: Report from the National Osteoporosis Foundation. J Bone Miner Res 12:24, 1997. 92. Recker, R.R.; Kimmel, D.B.; Parfitt, A.M.; et al. Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res 3:133, 1988. 93. Riggs, B.L.; Melton, L.J., III. Evidence for two distinct syndromes of involutional osteoporosis. Am J Med 75:899, 1983. 94. Riggs, B.L.; Melton, L.J., III. Involutional osteoporosis. N Engl J Med 314:1676, 1986. 95. Riggs, B.L.; Melton, L.J., III. The prevention and treatment of osteoporosis. N Engl J Med 327:620, 1992. 96. Riginster, J.; Minne, H.W.; Sorsenson, O.H.; et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83, 2000. 97. Rosen, C.J.; Kiel, D.P. The aging skeleton. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 57. 98. Rubin, C.T.; Rubin, J. Biomechanics of bone. In: Favus, M.J., ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 57. 99. Schneider, R.; Math, K. Bone density analysis: An update. Curr Opin Orthop 5:66, 1994. 100. Schnitzer, T.; Bone, H.G.; Crepaldi, G.; et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate OnceWeekly Study Group. Aging 12:1, 2000. 101. Scileppi, K.P.; Stulberg, B.; Vigorita, V.J.; et al. Bone histomorphometry in femoral neck fractures. Surg Forum 32:543, 1981. 102. Seeger, L.L. Bone density determination. Spine 22(Suppl 24):49S, 1997. 103. Shinoda, H.; Adamek, G.; Felix, R. Structure-activity relationships of various bisphosphonates. Calcif Tissue Int 35:87, 1983.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
436
SECTION I • General Principles Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, p. 257. 109. Weiss, N.S.; Ure, C.L.; Ballard, J.H.; et al. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 303:1195, 1980. 110. World Health Organization. Assessment of fracture risk and its application to screening for post-menopausal osteoporosis: Report of a World Health Organization Study Group. World Health Organ Tech Rep Ser 843:1, 1994.
104. Silver, J.J.; Einhorn, T.A. Osteoporosis and aging: Current update. Clin Orthop 316:10, 1995. 105. Smith, R.W., Jr.; Walter, R.R. Femoral expansion in aging women: Implications for osteoporosis and fractures. Science 145:156, 1964. 106. Steier, A.; Gegalia, I.; Schwartz, A.; Rodan, A. Effect of vitamin D and fluoride on experimental bone fracture healing in rats. J Dent Res 46:675, 1967. 107. Walsh, W.R.; Sherman, P.; Howlett, C.R.; et al. Fracture healing in a rat osteopenia model. Clin Orthop 342:218, 1997. 108. Wasnich, R.D. Epidemiology of Osteoporosis. In: Favus, M.J., ed.
Copyright © 2003 Elsevier Science (USA). All rights reserved.
