27: Osteoporosis & Hip Fractures

Osteoporosis is a skeletal disorder characterized by compromised bone strength, resulting in bone fragility and susceptibility to fractures. Bone strength is a function of bone mineral density (BMD) and bone quality. Bone quality refers to the architecture, bone turnover, damage accumulation, and mineralization occurring at the bony matrix. Bone mass is assessed with the use of bone density measurements; ie, dual x-ray absorptiometry (DXA), but currently there is no way to measure bone quality in a quantitative and comparable way.

Osteoporosis is a disease with its origin in childhood. Although genetic factors primarily account for peak bone mass, environmental factors such as nutrition and exercise can alter the genetically determined pattern of skeletal growth. At present, not enough is known about the genetics of osteoporosis to influence clinical decision making. However, it is known that illness and medications during a person’s lifetime can impact the accrual of peak mass such that individuals start at a lower peak bone mass. Modulation of peak bone mass can even occur during intrauterine life and is affected by maternal nutrition, smoking, and level of exercise. During adulthood, bone tends to have a steady state of formation and resorption with a stable bone mass. For women, menopause marks the start of increased bone resorption. For most older adults bone resorption exceeds bone formation, with acceleration of the process caused by medical illness and medications.

Older adults are particularly susceptible to the adverse outcomes attributed to osteoporosis. Comorobidities, such as cognitive and gait impairments, which are more prevalent as a patient gets older, predisposes the individual to falls and the development of fragility fractures.

According to the National Osteoporosis Foundation, the United States has some 52 million individuals with low bone mass: 9 million with osteoporosis and 43 million with osteopenia. The prevalence of osteoporosis and osteopenia increases with age for both men and women. With the growth in the geriatric population as a consequence of the coming of age of the baby boomers, the prevalence of osteoporosis and fractures is expected to increase exponentially.

An estimated 1.5 million fragility fractures occur in the United States each year. Approximately 50% of women and 20% of men older than age 50 years will have a fragility fracture in their remaining lifetime, with potentially devastating results. In general, osteoporotic fragility fractures involve the hip, vertebral, and wrist fractures. However, the effect of osteoporosis on the skeleton is systemic and there is an increased risk of almost all types of fractures in patients with low bone mass. It is estimated that the annual U.S. health care cost of fractures is approximately $20 billion, most of it attributed to acute care hospitalization followed by subacute rehabilitation. Although the overall prevalence of fragility fractures is higher in women, men generally have a higher rate of fracture-related mortality because of associated comorbidities. Even though vertebral fractures are the most prevalent of all fragility fractures, hip fractures contribute more to significant health care expenditure and are associated with the most serious outcomes.

Primary osteoporosis defines bone loss associated with the normal aging process; this occurs in both men and women. At the cellular level osteoblasts and osteoclasts work synergistically at a bone resorption pit to maintain bone homeostasis. Many proteins and hormones have been implicated in the pathogenesis including estrogen, vitamin D, and parathyroid hormone (PTH), all of which either increase bone resorption or reduce bone formation, such that the bone remodeling unit in a patient with osteoporosis has incomplete filling of the resorption pits. The primary regulator of bone remodeling is now recognized to be the receptor activator of nuclear factor kappa-B ligand (RANKL) produced by osteoblasts. RANKL binds to RANK receptors on osteoclast precursors and induces maturation as well as activity. Osteoblasts also produce osteoprotegerin (OPG) which blocks RANKL, thereby inhibiting osteoclast activity and maintaining bone homeostasis. This bone remodeling process serves to maintain calcium balance and to repair damage at the bony matrix.

Secondary osteoporosis is bone loss caused by a variety of diseases, conditions, or drugs. In the ambulatory and nursing home geriatric population, secondary hyperparathyroidism (caused by vitamin D deficiency) accounts for approximately 20% of secondary causes. With age there is decreased absorption of intestinal calcium and decreased renal calcium conservation, with a resultant increase in bone resorption as a result of increased PTH; thus calcium and vitamin D must be replaced aggressive in older adults. In 50–60% of men with osteoporosis, there is often a secondary cause—such as hypogonadal states during adolescence or adulthood; or the use of steroids or alcohol. Fifty percent of perimenopausal women also have secondary causes attributed to hypogonadal states or the use of medications such as steriods, thyroid therapy or anticonvulsant therapy.

Symptoms & Signs

Osteoporosis is generally a silent disease with no clinical manifestations until there is a fracture. Risk factors, the FRAX algorithm, a physical exam assessment, laboratory assessment, and imaging can potentially identify a patient who is at risk for osteoporosis.

Risk factors—

Several important common clinical risk factors for osteoporosis and falls have been identified through epidemiologic studies and indicate how closely each of the entities are codependent (Table 27–1). Approximately 95% of hip fractures are caused by falls and so risk factors for falls have to be considered.

Fracture risk assessment tool—

The FRAX algorithm, a fracture risk assessment tool developed by the World Health Organization, uses some of the above clinical risk factors, BMD measurements, and country-specific fracture data to calculate a patient’s 10-year probability of a fragility fracture. FRAX was developed to be applicable to both postmenopausal women and men ages 40 to 90 years. It is validated to be used in untreated patients only. The algorithm is accessible online for physicians to use in a primary care setting at www.sheffield.ac.uk/FRAX. The National Osteoporosis Foundation Clinician’s Guide recommends treating patients when they have a FRAX 10-year probability of hip fracture ≥3% or a 10-year probability of other major osteoporosis-related fracture ≥20%.

A literature review by Green and colleagues found no single physical examination finding or combination of findings sufficient to rule in osteoporosis or spinal fracture without further testing. Several examination findings including low body weight (<51 kg), inability to place the back of the head against a wall when standing upright, low tooth count (<20 count), self-reported humped back, and rib–pelvis distance ≤2 fingerbreadths can significantly increase the likelihood of osteoporosis or spinal fracture and identify additional women who would benefit from earlier screening. Height loss resulting from vertebral compression fractures can be measured in the clinic over time or using the patient’s recalled maximal adult height, can be potentially useful tool but the studies were not all in agreement as to its predictive value. Nevertheless, most experts would agree that a loss of height >3 cm should warrant further testing such as a lateral spine film or DXA scan.

Other pertinent physical exam findings should focus on secondary causes of osteoporosis, which will depend on the clinical history and identified risk factors. In the geriatric population, a comprehensive review of all used medications is essential.

Imaging Studies

Imaging studies are critical in osteoporosis not only to identify patients at risk, but also to monitor the effect of pharmacotherapy.

Chest and bone radiographs—

Osteoporosis is most commonly diagnosed by simple radiographs but the bone loss has to be >30% in order to be detected. The main radiographic features are radiolucency, cortical thinning, and occult fractures. Vertebral fractures are frequently asymptomatic and may easily be missed on radiographs that are obtained for other indications. Many studies have noted that vertebral fractures are inadequately reported and thus few of these patients receive appropriate osteoporosis-specific pharmacotherapy. Also during the past decade a number of publications have identified insufficiency fractures, especially at the medial femoral condyle of the knee and femoral head, which are frequent findings in older individuals and indicate increased fragility of the skeleton.

Patients on antiresorptive therapy who complain of bone pain should have radiographs of the affected site. Recently atypical subtrochanteric and femoral shaft fractures have been identified in older individuals and associated with long-term bisphosphonate therapy. These fractures have typical features that help to identify them, including location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, absence of comminution, cortical thickening, and a periosteal reaction of the lateral cortex.

Dual x-ray absorptiometry—

DXA measurement remains the gold standard to determine bone density, estimate fracture risk, identify candidates for intervention, and to assess changes in bone mass over time in treated and untreated patients. DXA is indicated in women age 65 years and older, as well as in younger and perimenopausal women with risk factors for fragility fractures. Medicare covers the cost in all older women (>65 years) for initial diagnosis and for follow-up after 2 years.

The International Society of Clinical Densitometry (ISCD) recommends BMD testing in all men age 70 years and older, and in men younger than age 70 years with clinical risk factors for fracture, including a prior history of a fragility fracture, a disease or condition associated with low bone mass or bone loss, and if taking medications associated with low bone mass or bone loss. The American College of Physicians (ACP) recommends that clinicians periodically perform assessment of risk factors for osteoporosis in older men, and that clinicians obtain DXA scans for men who are at increased risk for osteoporosis and are candidates for drug therapy.

The routine DXA examination includes results for the hip, spine, and wrist; BMD measurement at central sites (spine and hip); and provides reproducible values at important sites of osteoporosis-associated fractures. Peripheral sites can also identify patients with low bone mass and predict fracture risk.

Bone density data are reported as T scores and Z scores. In 1994, the World Health Organization (WHO) used T scores to classify and define BMD measurements (Table 27–2). The definitions, originally only for postmenopausal women, have been adapted by the ISCD to classify BMD in premenopausal women, men, and children. Each standard deviation change in the BMD increases fracture risk by 2–2.5 times.

Annual losses of bone mass normally seen with aging are in the range of 1% per year, the precision error of current instruments (approximately 1% to 2% with DXA) means that the interval between scans should be at least 2 years. Patient with high-dose steroid therapy can have rapid bone loss in a shorter interval and annual scans should be obtained.

DXA has some disadvantages. It is a 2-dimensional measurement, which only measures density/area and not the volumetric density. Areal BMD is influenced by bone size and will overestimate fracture risk in individuals with small body frame, who will have lower BMD. Spine and hip DXA are also sensitive to degenerative changes, and individuals with considerable degenerative disease will have increased density, suggesting a lower fracture risk than is actually present. All structures overlying the spine, such as aortic calcifications, or morphologic abnormalities, such as after laminectomy, will affect BMD measurements and thus need to be considered when reviewing DXA results.

Laboratory Evaluation

Laboratory testing in patients with presumed osteoporosis are usually undertaken to rule out or find common secondary causes of osteoporosis. Preliminary testing should include basic chemistry panel; a complete blood count; and liver function panel. Patients who have Z scores less than −2 standard deviations (SD) from their age-matched cohorts or who have physical findings, should be assessed for more specific secondary causes of osteoporosis (Table 27–3). It is important to note in the geriatric population secondary hyperparathyroidism caused by vitamin D deficiency is prevalent and all older patients should have a 25-hydroxy vitamin D and PTH assessment.

Bone turnover markers—

Additional laboratory testing includes bone turnover markers (BTMs), which are traditionally categorized as bone formation or bone resorption markers (Table 27–4). Their routine use in clinical practice remains a challenge because of their wide biologic and analytical variability. It should be noted that resorption markers must be measured in the morning on the second void urine because there is a large diurnal variation.

The best established clinical use for BTMs is in monitoring treatment efficacy and compliance. Antiresorptive agents rapidly decrease BTMs. On average, BTMs change by 50% following antifracture treatment, making it easier to use in monitoring treatment efficacy within months compared to BMD changes, which take years. The resorption markers are also independent risk factors for fracture.

Osteoporosis results in massive costs both to the individual and to society through associated fragility fractures. A fracture is considered to be osteoporotic (fragility fracture) if it is a result of relatively low trauma, such as a fall from standing height or less, or use of a force that in a young healthy adult would not be expected to cause a fracture. The most common sites of fragility fractures are the hip, spine, and distal forearm. The presence of 1 or more low-impact fragility fractures is considered as a sign of severe osteoporosis and often the BMD measured may be in the normal or osteopenic range.

Hip Fracture

Hip fracture incidence increases with age and typically peaks after age 85 years. With increasing life expectancy, and hip fracture incidence rates rising exponentially with age, this will result in an emergent number of hip fractures. In 2004, there were approximately 329,000 hip fractures in the United States and about one-third occurred in men.

In general, men have poorer outcomes after hip fracture than women. Mortality rates are doubled in men, with approximately 32% of men dying within a year of a hip fracture. This disparity in mortality may be attributed to increased comorbidities and more postoperative complications in men. Men also have poorer functional recovery in physical activities 1 year after the hip fracture. Of those who were not institutionalized before fracture, 25% remain in an institution a year or longer after fracture.

Hip fractures are classified by the area of femur affected and by whether displacement is present. The types of hip fracture are intracapsular fractures, intertrochanteric fractures, and subtrochanteric fractures. The injured leg is often shortened, externally rotated and abducted when the patient is lying flat. Plain radiographs are diagnostic, but in a few instances of a negative radiograph, obtaining a MRI is helpful to evaluate for an occult fracture.

Surgery remains the main therapeutic option and provides the best opportunity for functional recovery. Conservative therapy can be considered in a patient with a nondisplaced femoral neck fracture or for patients too ill to undergo surgery. A displaced intracapsular fracture is likely to have vascular compromise to the head of the femur, resulting in non-union and osteonecrosis, and thus often require hemiarthroplasty. Intertrochanteric and subtrochanteric fractures can be treated with internal fixation with sliding screws or nails.

Vertebral Fracture

The incidence of all vertebral fractures has been estimated to be 3 times that of hip fracture. Both the prevalence and incidence of radiographic vertebral fractures increase with age. Among white women, the prevalence of vertebral fractures increases from 5% to 10% between the ages of 50 and 59 years and to >30% at 80 years of age or older.

Multiple vertebral fractures can lead to increased thoracic kyphosis with height loss and development of “dowager’s hump”; protuberant abdomen as internal organs are contained in a smaller compartment; complaints of pain in the muscles of the neck because patients must extend the neck to look forward; reduction in the distance between the bottom of the rib cage and the top of the iliac crests, which may be associated with dyspnea and gastrointestinal complaints (eg, early satiety and constipation); functional and physical limitation because of chronic pain, which leads to anxiety, depression, and loss of self-esteem and self-image.

Lateral thoracic and lumbar spine radiographs are the standard tool for assessment. Differential diagnoses for vertebral deformities are malignancy; metabolic bone diseases; degenerative disease; Scheuermann disease; Paget disease; hemangioma; infection; and dysplastic changes.

Data from randomized, controlled trials (RCTs) evaluating the efficacy of pain medications for acute vertebral fracture are lacking. Nonsteroidal antiinflammatory drugs, analgesics (including narcotics and tramadol), transdermal lidocaine, and tricyclic antidepressants are commonly used. Although the pain typically subsides over several weeks, narcotics are often required to facilitate mobility and avoid prolonged bed rest. Calcitonin has been found to modestly reduce pain associated with an acute vertebral fracture. Limited evidence also supports the use of therapeutic exercise programs to reduce pain and improve strength, balance, functional status, and quality of life.

Two recent procedures being performed on patients with acute vertebral fractures to relieve pain are kyphoplasty (inflating a small balloon at the site of a compression deformity to reduce the pressure) and vertebroplasty (placing cement at the site of a compression deformity). Often the 2 procedures are performed consecutively to minimize extravasation of the cement material. Observational studies noted reduced pain, disability and length of hospital stay; however, a RCT with a sham procedure showed no benefit.

Wrist Fracture

Wrist fractures show a pattern of occurrence that differs from that of hip and vertebral deformities. The incidence of this type of fracture increases in white women from the age of 45 to 60 years, followed by a plateau. Wrists fractures are generally associated with a fall from an outstretched arm.

A recent review article summarized that having had a previous hip fracture was likely to increase the risk of another fracture 3-fold, and of a hip fracture nearly 4-fold, and the lifetime risk of another vertebral fracture was 4-fold higher. Thus, secondary prevention after any fragility fracture should focus on fall prevention and treatment for osteoporosis since further fragility fractures are likely to occur.

Effective therapies for prevention of osteoporosis and fractures are now available.

Peak Bone Mass

Attainment of peak bone mass is primary in preventing osteoporosis and fractures in adulthood. This includes modification of general lifestyle factors, such as a balanced diet containing calcium and vitamin D, regular exercise, smoking cessation and avoidance of heavy alcohol use.

Exercise

A Cochrane analysis noted that aerobics, weight-bearing, and resistance exercises were all effective on the BMD of the spine. Walking was also found to be effective on both BMD of the spine and the hip and should be encouraged. Long-term studies to determine fracture data are required.

The positive implications of exercising in the geriatric population extend far beyond improvements in BMD: prevention of falls through improvements in muscle strength, balance and posture control; increase in fitness and quality of life; and decrease in pain intensity and frequency at the spine.

Fall Prevention

Falls prevention is integral in fracture prevention (see Chapter 25, “Falls & Mobility Disorders”).

Hip Protectors

Hip protectors consist of a hard or soft shell with a soft padding that covers the area over the greater trochanter of the hip. Their use should be encouraged for patients at increased risk, especially those in a nursing home. Compliance remains an issue.

Calcium Supplementation

The Institute of Medicine (IOM) recommends a total daily elemental calcium intake of 1000 mg for all adults 19–50 years old, including pregnant and lactating women, 1000 mg for men 51–70 years old, and 1200 mg for women >50 years old and men >70 years old.

Calcium supplements are available as salts with varying concentrations of elemental calcium. Calcium citrate does not require acid for absorption, can be taken with or without food, and is preferred in patients taking proton pump inhibitors or H₂-receptor antagonists, or in those with achlorhydria. Calcium carbonate should be taken with food and in divided doses to enhance absorption.

Calcium supplements are generally well tolerated but constipation, intestinal bloating and excess gas can occur. A slightly higher risk of kidney stones has been reported. Some reports suggest that calcium supplementation increases the risk of cardiovascular disease, but the data is inconsistent with most prospective studies not depicting an increased risk. Calcium supplementation can increase BMD in children and adolescents, and reduce bone loss in postmenopausal women and older men.

Vitamin D Supplementation

Vitamin D is necessary for optimal absorption of calcium. Older adults often do not produce adequate amounts through cutaneous production or from the diet. Vitamin D deficiency is associated with muscle weakness, and can predispose a person to falls.

Vitamin D status can be evaluated by measuring serum 25-hydroxy vitamin D (25-OH-D); a level of ≥30 ng/mL is considered acceptable; ≤10 ng/mL is considered severe deficiency or osteomalacia; and a range between 10 and 30 ng/mL is considered an insufficiency when accompanied by a notable rise in serum PTH. The IOM recommends a dietary allowance of vitamin D of 600 IU daily for people up to 70 years old and 800 IU daily for those ≥71 years old. Hypercalciuria and hypercalcemia can be seen with vitamin D toxicity.

The Women’s Health Initiative (WHI) reported a reduction in fractures among the women who were adherent to calcium and vitamin D supplementation. The antifracture effect of vitamin D is more pronounced in the institutionalized and involves its effect on muscle strength and falls prevention.

Guidelines by the National Osteoporosis Foundation (NOF) recommend osteoporosis treatment in postmenopausal women or men age 50 years and older with a T-score of less than −2.5 at the femoral neck, hip, or spine; patients with low bone mass (T-score between −1.0 and −2.5) and a 10-year probability of hip fracture of ≥3% or a 10-year probability of major osteoporosis-related fracture of ≥20%, as determined by FRAX; and in patients with a fragility fracture.

Current osteoporosis therapy are divided into antiresorptive and anabolic agents (Table 27–5). Antiresorptive therapy available in the United States are bisphosphonates, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), denosumab, and calcitonin. Parathyroid hormone is the only anabolic agent available in the United States.

Bisphosphonates

Bisphosphonates are potent antiresorptive agents that bind hydroxyapatite crystals on bone surfaces and permanently inhibit osteoclast function. FDA-approved agents are alendronate, risedronate, ibandronate and zoledronic acid.

Bisphosphonates may be given orally on a daily (alendronate, risedronate), weekly (alendronate, risedronate), or monthly (risedronate, ibandronate) schedule or intravenously every 3 months (ibandronate) or intravenously once yearly (zoledronic acid). Oral bisphosphonates must be taken on an empty stomach because of their poor absorption and bioavailability. Patients must sit upright and fast for 30 minutes (with alendronate and risedronate) to 60 minutes (with ibandronate) after ingestion. Prior to the initiation of any bisphosphonates therapy, calcium and vitamin D must be adequately repleted because of the possibility of inducing hypocalcemia, especially in older adults.

Oral bisphosphonates are commonly associated with gastrointestinal side effects, including dyspepsia, heartburn, indigestion, and pain while swallowing. More serious gastrointestinal effects include erosive esophagitis and esophageal ulcerations; thus patients are reminded to take a full glass of water (6–8 oz) and remain upright after the dose. Acute phase reactions (fever, myalgia, arthralgia, headache, and flu-like symptoms) have been reported with both oral and intravenous bisphosphonates. Intravenous zoledronic acid has been associated with acute renal failure and should be used with caution in patients with renal impairment. Alendronate should also be used with caution in patients with severe renal insufficiency (creatinine clearance <35 mL/min). Long-term effects, including osteonecrosis of the jaw and atypical fracture, are rare and benefits from fracture reduction outweigh the harms.

All bisphosphonates have been shown to significantly improve BMD of the spine and reduce risk of vertebral and hip fractures. There are no published data for hip fracture reductions with ibandronate in randomized clinical trials. There are no studies of comparative efficacy of the bisphosphonates with each other.

The duration of bisphosphonate therapy is not yet clear. Seven-year follow-up of patients using alendronate showed that spinal BMD continued to increase through 7 years of treatment and remained stable. After the withdrawal of treatment, there was a small increase in biochemical markers of bone turnover. It appears that skeletal benefits may be preserved for at least 1–2 years after cessation, but long-term follow-up studies are needed.

Hormone Replacement Therapy

Hormone replacement therapy (HRT) is approved for the prevention of osteoporosis in postmenopausal women, although the primary indication is for the treatment of moderate-to-severe menopausal symptoms. The exact mechanism of HRT on bone remodeling has not been elucidated, however it is clear that the loss of estrogen during menopause results in an acceleration of bone resorption in most women.

Combined estrogen and progesterone therapy have produced a 1.4% to 3.9% increase in BMD at skeletal sites. Studies have shown that estrogen reduces the risk for vertebral and hip fracture, as well as the risk of nonvertebral fracture. In the WHI trial, treatment of postmenopausal women with combined therapy reduced the risk of hip fracture by 33%.

The timing of initiation and duration of HRT remains unclear. It is suggested that women start estrogen within 2–7 years of menopause. Several studies have shown that HRT begun before 60 years of age prevents nonvertebral, hip, and wrist fractures, but there is insufficient evidence that fracture risk is reduced when HRT is begun after age 60 years. Estrogen begun and continued after age 60 years appears to maintain BMD. The duration of therapy necessary to protect women against fragility fractures is indefinite. HRT can be administered as an oral or transdermal formulation. It may be given on a continuous basis, with no interruption in therapy, or as a cyclical regimen.

Compliance with HRT is typically poor because of common side effects and concern about increased incidence of breast or endometrial cancer. Women who have not undergone hysterectomy should have progestin added to the estrogen regimen to prevent endometrial hyperplasia. Low-dose HRT can reduce the amount of uterine bleeding, fluid retention, mastalgia, and headaches, making estrogen therapy much easier to tolerate.

Safety results from the WHI study showed an increased risk of coronary heart disease, pulmonary embolism, and stroke associated with the use of combined hormonal therapy in women with an intact uterus. As a result, HRT is considered second line therapy for only prevention of osteoporosis in young perimenopausal women with menopausal symptoms.

Selective Estrogen Receptor Modulators

SERMs are compounds that bind to and activate estrogen receptors but have agonist/antagonist properties at different tissue sites. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis and indicated for the reduction of invasive breast cancer.

Raloxifene at 60 mg per day has been shown to increase BMD by 2% and reduce the risk of new vertebral fracture by 40% after 2 years. However, raloxifene has not demonstrated a protective effect on nonvertebral or hip fracture risk.

Calcitonin

Calcitonin, an endogenous hormone secreted by the parafollicular C cells of the thyroid gland, which helps to maintain calcium homeostasis. Calcitonin acts directly on osteoclasts, with inhibitory effects on bone resorption. Calcitonin is approved for the treatment of postmenopausal osteoporosis. Calcitonin nasal spray has been shown to have modest effects on spine BMD (1.5% increase) and significantly reduce the risk of new vertebral fractures by 33% in women with prevalent vertebral fractures. There was no significant effect on hip or nonvertebral fracture risk. Calcitonin is an option for women who cannot tolerate bisphosphonates or SERMs. In some patients, calcitonin has an analgesic effect, making it suitable for patients with acute vertebral fracture. Calcitonin nasal spray is generally administered once per day, alternating nostrils daily. Injectable calcitonin can be administered subcutaneously or intramuscularly.

Denosumab

Denosumab is a human monoclonal antibody with a high affinity and specificity for RANKL. When denosumab binds to RANKL, it prevents RANKL–RANK interaction resulting in a decrease in osteoclastic bone resorption.

Denosumab is approved for osteoporosis treatment. Results from phase 3 study in women with osteoporosis showed that treatment with denosumab increased lumbar spine BMD by 6.5%, and significantly reduced the risk of vertebral (68%) and hip (40%) fractures compared with placebo. Prior to starting denosumab, patients with preexisting hypocalcemia must have this condition corrected because it could worsen with treatment. Denosumab may be given to patients with renal impairment without dose adjustment.

Parathyroid Hormone

Teriparatide is an FDA-approved anabolic agent that is synthetic PTH. It stimulates bone remodeling, preferentially increasing formation over resorption, and reduces the risk of new vertebral fractures (65% reduction) and nonvertebral fractures (35%) with significant improvements in BMD of 10% to 14%.

Teriparatide is administered as daily subcutaneous injections. Eleven percent of patients developed mild hypercalcemia. Osteosarcomas have been induced in rats given teriparatide. However, an independent oncology advisory board concluded that the rat carcinogenicity data are very unlikely to have clinical relevance in humans being treated with teriparatide for a relatively short duration (it is approved for only 2 years’ use).

Upon termination of teriparatide treatment, sequential therapy with an oral or IV bisphosphonate may strengthen the beneficial effects of teriparatide. Concurrent therapy with teriparatide and oral bisphosphonates has been avoided because oral bisphosphonates have been shown to reduce the positive effects of teriparatide on bone turnover.

In summary, given a choice of pharmacotherapy, clinical risk factors for fracture and comorbidities should be taken into account when tailoring therapy for osteoporosis. Risk factors such as age and previous fracture are critical to choosing an optimal treatment strategy. Clinicians need to be aware of the safety concerns associated with each drug and treatment should be made on an individual basis taking into account the relative benefits and risks in different patient population.