Chapter 194 Osteoporosis
Diagnostic Summary
General Considerations
Osteoporosis is the most common bone disease in humans and poses a serious health threat for postmenopausal women. It is characterized by diminished bone strength, which leads to an increased risk of fracture. Bone mineral density (BMD) is a major determinant of bone strength and is the most commonly measured quality of bone. Osteoporosis is determined by bone densitometry and, according to the World Health Organization (WHO), is defined by a a BMD T-score less than or equal to -2.5 at the total hip, femoral neck, or lumbar spine (with at least two vertebral levels in the posteroanterior position) in a postmenopausal woman or a man over age 50.1,2 Most other organizations support this description. The presence of a fragility fracture also justifies a clinical diagnosis of osteoporosis.
Osteoporosis most commonly occurs in postmenopausal women, and the risk increases with age. Although the prevalence is 4% in women between 50 and 59 years of age, it rises to 52% in women age 80 and above.3 Osteoporosis of the hip occurs in 13% to 18% of white American women and another 37% to 50% have low bone mass (often called osteopenia) of the hip.4
Osteoporosis is responsible for approximately 90% of all hip and spine fractures in white American women ages 65 to 84.5
However, most postmenopausal women who have fractures at any site do not actually have a diagnosis of osteoporosis.6
The hip is not the only site where fractures result in serious morbidity. Vertebral fractures occur in a woman’s mid-70s and cause significant pain as well as loss of height and an exaggerated kyphosis or deformity of the thoracic spine. In addition to pain, restricted range of motion, changes in posture, restricted lung function, and digestive problems can all be caused by vertebral fractures of the thoracic or lumbar region or both. Other tolls can accumulate because of osteoporosis. Depression, anxiety, low self-esteem, changed body image, and loss of independence are other burdens of this disease. Once a vertebral fracture has occurred, there is at least a five- to sevenfold increase in the risk of subsequent vertebral fractures.7,8
Although not commonly recognized, men are also at risk of osteoporosis as they age. Hip fractures in men account for one third of all hip fractures and have a higher mortality than those in women.9
Pathophysiology
Risk Factors
• Thinness—weight below 127 pounds
• Parental history of hip fracture
• Long-term use of glucocorticoids
• Other causes of secondary osteoporosis (e.g., primary hyperparathyroidism, renal calcium leak)
• Alcohol intake above two units daily
Genetic Factors
The level of peak bone mass is greatly influenced by genetic factors. Earlier studies suggest that up to 80% of the determination of peak bone mass might be due to genetic factors.10–12 Young daughters of women with osteoporotic fractures have lower bone mass compared with other children their age, and first-degree relatives of women with osteoporosis tend to have lower bone mass when compared with other women who do not have such a family history.13 A history of fracture in a first-degree relative also increases fracture risk. A family history of fracture was found to be associated with a significant increase in osteoporotic fractures at any site.14 In this same meta-analysis, hip fractures were almost 50% higher if a family had a history of fractures and 127% higher if a hip fracture had occurred in a parent. The greater bone mass of black women compared with white women also suggests a genetic influence.
Lifestyle
Calcium and vitamin D intake, exercise, age at menarche, menstrual regularity, and alcohol and tobacco use also affect peak bone mass. All women lose bone mass in menopause, but several lifestyle factors affect the risk of developing osteoporosis, including physical activity, animal protein intake, acid-base homeostasis, calcium and vitamin D intake, smoking, and alcohol consumption. In order for a woman to achieve her genetically determined peak bone mass, she requires a balanced diet including adequate calories, protein, and calcium.16 Good nutrition throughout life is necessary to maintain bone mass and strength. Adequate calcium and vitamin D have crucial roles in maintaining bone mass in older women. Calcium requirements change with age; during and after menopause, the need for calcium increases. After age 65, women absorb 50% less calcium than younger women. The renal enzymatic activity that produces vitamin D metabolites and thus controls calcium absorption also decreases.
Dietary Protein
Not all studies have been consistent regarding whether or not excess dietary protein contributes to osteoporosis. The Nurses’ Health Study showed that a high intake of animal protein but not plant protein was associated with an increased risk of forearm fracture.17 Diets high in red meat are acid producing, and salts from bone may be mobilized to balance the acid and maintain the acid-base homeostasis the body requires. Diets high in fruits, vegetables, and plant proteins are alkaline forming.
Smoking
Female smokers tend to lose bone more rapidly and have a lower bone mass than those who do not smoke.18,19 Some studies show that smokers also have a higher fracture rate.20,21 In addition, female smokers reach menopause up to 2 years earlier than nonsmokers. It may be that smoking interferes with estrogen metabolism, although the mechanism is not clearly known.
Alcohol
Alcohol consumption of 7 ounces or more daily, which is considered heavy, has been shown to increase the risk of falls and hip fractures. However, moderate alcohol consumption seems to lower the risk of hip fractures in older women.11 It is thought that moderate amounts of alcohol inhibit bone resorption by increasing estradiol concentrations and calcitonin excretion.22,23
Physical Activity
The effect of physical activity on the risk of osteoporosis cannot be overlooked. Highly active individuals have higher bone mass,24 and those who have undergone prolonged bed rest or are confined to a wheelchair experience a rapid and dramatic loss of bone. Exercise functions primarily to reduce osteoporosis risk by stimulating osteoblasts.
Hormonal Factors
A woman’s hormonal status clearly influences bone mass and the rate of bone resorption. At menopause, all women lose bone, and this loss is especially accelerated in the first 5 years. The drop in estrogen production that comes with menopause, no matter the age, increases the rate of bone resorption. The earlier that occurs before the average age of menopause (51 years), the sooner the bones lose the protective effect of endogenous estrogen.
Women who have premature menopause (before age 40), late onset of menarche in adolescence, surgical menopause, or experienced periods of amenorrhea due to low estrogen levels in their reproductive years (ex/hypothalamic amenorrhea), are at greater risk of osteoporosis if they have not taken longer term estrogen replacement therapy. Women who had missed up to half of their expected menstrual periods had 12% less vertebral bone mass than did those with normal menstrual cycles; those who missed more than half had 31% less bone mass than healthy controls.25
Diagnostic Considerations
The history and physical examination should focus on identifying the woman’s risk factors. There can be physical signs of osteoporosis. Loss of height greater than 1.5 inches may be associated with compression of vertebrae due to fractures on the anterior vertebral body. Measurement of height annually is the simplest of procedures that can be used to identify the risk of osteoporosis. Excessive kyphosis of the thoracic spine, dowager’s hump, dental caries, tooth loss, receding gums, and back pain should raise suspicion of osteoporosis. Weight should also be recorded to identify women with low BMI and thus increased risk for low bone density. Other aspects of evaluation should including the solicitation of acute or chronic back pain, signs of percussion tenderness on exam, and bone density testing. The risk of falls should be assessed and is increased by the following: medications that affect balance and coordination, muscle weakness, impaired vision, a history of falls/fainting or loss of consciousness, difficulty standing or walking, arthritis of the lower extremities, and neuropathy of the lower extremities.
Bone Mineral Density Testing
BMD testing is the optimal method to establish a diagnosis of osteoporosis. There are several techniques to measure BMD, but the gold standard is dual energy x-ray absorptiometry (DEXA).26 Other methods of assessing bone mass include computed tomography (CT), ultrasounds of the heel, and radiographs, none of which is as useful for diagnosis and follow-up as the DEXA scan. The tests that measure BMD and their relative accuracy are shown in Table 194-1.
TABLE 194-1 Comparison of Tests Measuring Bone Density
| METHOD | SITE AND ACCURACY |
|---|---|
| DEXA | Hip, spine, total body: 90%-99% |
| PDXA | Forearm, finger, heel: 90%-99% |
| SXA | Heel: 98%-99% |
| QUS | Heel, shin: not available |
| QCT | Spine: 95%-97% |
| PQTC | Forearm: 92%-98% |
DEXA, Dual-energy x-ray absorptiometry; PDXA, peripheral dual-energy x-ray absorptiometry; PQTC, peripheral quantitative computed tomography; QCT, quantitated computed tomography; QUS, quantitative ultrasound; SXA, single-energy x-ray absorptiometry.
Data from Jergas M, Genant HK. Current methods and recent advances in the diagnosis of osteoporosis. Arthritis Rheum 1993;36:1649-1662.
• All women 65 years of age and older
• Postmenopausal women with secondary causes of bone loss (e.g., steroid use, hyperparathyroidism)
• Postmenopausal women age 50 and above with additional risk factors (fracture after menopause, thinness or weight below 127 pounds, history of hip fracture in a parent, current smoker, rheumatoid arthritis, alcohol intake of more than two units per day [one unit being equal to 12 ounces of beer, 4 ounces of wine, or 1 ounce of liquor])
• Postmenopausal women regardless of age with postmenopausal fragility fractures, low body weight, or a family history of spine or hip fracture
Results of BMD tests are reported as standard deviations—either a Z-score or a T-score. A Z-score is based on the standard deviation from the mean BMD of women in the same age group. A T-score is based on the mean peak BMD of a normal young woman. The WHO criteria for the diagnosis of osteoporosis are based on T-scores, as shown in Table 194-2.
TABLE 194-2 Interpretation of Bone Mineral Density Score
| STATUS | T-SCORE | INTERPRETATION |
|---|---|---|
| Normal | Above -1 | BMD within 1 SD of a young normal adult’s T-score |
| Osteopenia | Between -1 and -2.5 | BMD between 1 and 2.5 SD below a young normal adult’s T-score |
| Osteoporosis | Below -2.5 | BMD 2.5 SD or more below a young normal adult’s T-score |
BMD, Bone mineral density; SD, standard deviation.
Laboratory Tests of Bone Metabolism
Biochemical markers of bone turnover appeal to some practitioners. A urine test measures the breakdown products of bone, such as cross-linked N-telopeptide of type I collagen or deoxypyridium. These tests measure bone turnover and can be correlated with the rate of bone loss, but they are not intended to be used for the diagnosis of osteoporosis or monitoring of bone loss. Such tests may be used to monitor the success (or failure) of therapy. They provide quicker feedback compared with DEXA, with which it can take up to 2 years to detect a therapeutic response. The DEXA test is best used to measure bone density, whereas urinary bone resorption assessments can be used to measure the rate of bone turnover. The reduction of urinary levels of these markers of bone breakdown over a 2-year period has produced increases in bone density measurements,27 but the value of these markers in clinical practice has yet to be definitively confirmed.
Management Approaches Based on Testing
1. All postmenopausal women who have had an osteoporotic vertebral or hip fracture
2. All postmenopausal women who have BMD values equal to or less than -2.5 at the lumbar spine, femoral neck, or total hip region.
3. All postmenopausal women who have T-scores from -1.0 to -2.5 and a 10 year risk, based on the FRAX calculator of major osteoporotic fracture (spine, hip, shoulder or wrist) of at least 20% or a hip fracture of at least 3% are at high risk, and drug therapy is recommended.
Therapeutic Considerations
The primary goals in the treatment and prevention of osteoporosis are as follows:
The primary role of alternative therapies is to prevent osteoporosis and, fortunately, osteoporosis is largely a preventable disease. Pharmacologic therapy reduces the risk of vertebral and hip fractures by about 50%. According to the North American Menopause Society and their 2010 position statement on osteoporosis, the following guidelines are indications for pharmacologic therapy28:
• All postmenopausal women who have had an osteoporotic vertebral or hip fracture
• All postmenopausal women who have BMD values consistent with osteoporosis (i.e., BMD T-score values equal to or less than -2.5) at the lumbar spine, femoral neck, or total hip region
• All postmenopausal women who have T-scores from -1.0 to -2.5 and a 10-year risk based on the FRAX calculator of major osteoporotic fracture (spine, hip, shoulder, or wrist) of at least 20% or of hip fracture of at least 3%
Pharmacologic Therapy
Hormone Replacement Therapy
As estrogen levels decline, bone remodeling increases and bone resorption outpaces bone formation. Both estrogen replacement therapy (ERT) with estrogen only and hormone replacement therapy (HRT), with estrogen and progestogen, reduce the rate of bone turnover and resorption.29
ERT can return the high resorption rates in postmenopausal women to those of the rates in premenopausal women. Long-term data on the effects of ERT and HRT on bone density and fracture risk come mainly from observational and epidemiologic studies. Epidemiologic research found a 54% reduction in risk of fractures in current users of ERT/HRT compared with those who never used it.30 Researchers also found that ERT/HRT is more effective in reducing the fracture risk if it is begun within 5 years of menopause. If it was used more than 10 years earlier, it produced an even greater risk reduction—75% for wrist fractures and 73% for hip fractures.
A 2002 meta-analysis of 57 randomized clinical trials of systemic oral or transdermal estrogen and estrogen/progestogen at standard doses found BMD increases at all sites in postmenopausal women.31 In trials of 2 years in length, the average difference in BMD after estrogen or estrogen/progestogen was 6.8% at the lumbar spine and 4.1% at the femoral neck.
The two largest and best-controlled trials are the Postmenopausal Estrogen/Progestin Interventions (PEPI) trials and the Women’s Health Initiative (WHI). In the PEPI trials, 0.625-mg daily doses of conjugated equine estrogens with or without a progestogen (either medroxyprogesterone acetate or oral micronized progesterone) for 3 years significantly increased spinal BMD by 3.5% to 5.0%; there was also a 1.7% increase in hip BMD.32 In the 5-year randomized controlled trial, the WHI HRT significantly increased spine BMD by 4.5% and total hip BMD by 3.7% in comparison with placebo; it also reduced the risk of hip fractures (34%), vertebral fractures (34%), and total body fractures (24%).33
Doses even lower than the standard dosages of estrogen have produced significant increased in spine and hip BMD in the range of 1% to 3%,34–38 as has systemic estrogen via a vaginal ring (the Femring).39
In addition to increases in BMD, randomized trials and observational studies have indicated that standard doses of estrogen or estrogen/progestogen reduce fracture risk in postmenopausal women. Two meta-analyses found up to a 27% reduction in fracture risk.40,41 Two large observational studies, the National Osteoporosis Risk Assessment study42 of over 200,000 women and the Million Women Study43 of over 138,000 women both reported significantly reduced risks for fractures. Despite these studies and more, estrogen-only or estrogen-plus-progestogen products are approved for prevention but not treatment of postmenopausal osteoporosis.
Bisphosphonates
This class of drugs is thought to work by inhibiting osteoclast activity, thereby reducing bone resorption. Clinical trials demonstrate that bisphosphonates can significantly increase BMD at the spine and hip in postmenopausal women no matter their age. Bisphosphonates have been shown to reduce the risk of vertebral fractures in women with osteoporosis, by 40% to 70% and to reduce the incidence of hip fracture and other nonvertebral fractures by about half of this.44,45 Most of the bisphosphonates available in the United States (alendronate, ibandronate, and risedronate) are intended for use in daily or intermittent oral doses. Zoledronic acid is available as an intravenous injection. Clinical trials that have demonstrated BMD responses show similar results for weekly oral dosing regimens of alendronate and risedronate, monthly oral dosing of ibandronate and risedronate, and intravenous dosing every 3 months of ibandronate.46–49
Bisphosphonates are not without problems and they should only be used with careful consideration—both for their potential benefit in women who have osteoporosis and are at higher risk for fracture (especially as they get older) and for their potential for serious risk. Some questions have arisen regarding the quality of the bone and possibly increased fractures with bisphosphonates in longer-term use in some individuals.50 There may be the potential for over suppression of bone turnover with long-term therapy, resulting in a more brittle bone. Individual cases and small case series with unusual, poorly healing fractures have been reported recently, as well as atypical fractures of the femur. Research is under way to determine what is unique to these rare individuals. Many clinicians are responding to these concerns by “drug holidays.” Understanding the frequency and duration of these drug holidays is under investigation in ongoing studies.
Osteonecrosis of the jaw (ONJ) has been observed with bisphosphonate use.51 This has occurred mainly in individuals on high-dose intravenous bisphosphonates and in those being treated with radiation for head and neck cancers. ONJ is characterized by a delay in healing of an oral lesion after surgery or extraction for more than 6 to 8 weeks. The incidence of ONJ with intravenous bisphosphonates in those without neck radiation has been reported to be as high as 12%. Oral incidence is much lower, at 0.03% to 0.06%. However, oral surgery increases the incidence sevenfold.52 Currently, there is controversy in the research on whether to discontinue bisphosphonate therapy before dental extraction. Many practitioners are recommending suspending bisphosphonate therapy until the oral lesion has healed.
Although not common, long-term bisphosphonate use is also associated with insufficiency fractures of the femoral shaft, which commonly presents with prodromal thigh pain and may be bilateral.53 This is one reason why the use bisphosphonates is now being recommended for a maximum of 5 years, which then allows bone remodeling.54 Bone density should be monitored closely to ensure stable or minimal bone loss after discontinuation. It appears that 5 years of use may provide long-term fracture protection just as effectively as the drug taken for more than 5 years.
Selective Estrogen-Receptor Modulators
Selective estrogen-receptor modulators (SERMs) are nonsteroidal estrogen agonists and/or antagonists. Raloxifene, at a dose of 60 mg/day, is approved for the prevention and treatment of osteoporosis. Currently, this is the only SERM approved for the treatment of osteoporosis. In a 20-year study, raloxifene at 60 mg/day significantly improved BMD at the lumbar spine by 1.6% and at the femoral neck by 1.2%.55 In the Multiple Outcomes of Raloxifene Evaluation trial, 3 years of raloxifene therapy at 60 mg/day in postmenopausal women increased BMD by 2.6% at the spine and 2.1% at the femoral neck.56
Parathyroid Hormone
Parathyroid hormone is given by subcutaneous injection once daily. This anabolic agent stimulates osteoblastic bone formation and increases trabecular bone density in women with osteoporosis.57–59 One medication in particular, teriparatide (Forteo) is approved for the treatment of osteoporosis in postmenopausal women. Nineteen months of teriparatide treatment (20 mcg/injection per day) increased bone density in the spine by 8.6% and in the femoral neck by 3.5% compared with placebo.59 In addition, the incidence of new vertebral fractures was reduced by 65% and nonvertebral fractures by 53%.
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