Osteoporosis is a skeletal disorder that compromises bone strength and can cause an increased risk for fracture. The estimated number of individuals with osteoporosis and osteopenia, the precursor to osteoporosis, continues to increase. The National Osteoporosis Foundation (NOF) estimates that more than 10 million Americans currently have osteoporosis, and another 33.6 million have osteopenia of the hip.1 Most fractures occur in patients who have osteopenia, not those with osteoporosis, thus early identification of low, bone mass is crucial.2 Given the potentially devastating effects of osteoporosis-related fractures (see Potential effects of osteoporosis-related fracture), educating patients about the prevention of bone loss, screening to identify bone loss early, and working with patients to develop effective management plans for osteoporosis or osteopenia are critical.

Figure. No caption available.

Bone strength encompasses both bone quality and bone density.3 Bone strength is affected by many factors (see Factors affecting bone strength).2,4 Some factors, such as lifestyle, can be controlled or modified by limiting alcohol consumption, not smoking, engaging in weight-bearing and resistive exercise, meeting intake recommendations for calcium and vitamin D (either through diet or supplementation), and preventing falls. These factors are key patient education points that help prevent bone loss and fracture. Others, such as heredity, genetic make-up, the patient's gender, and disease states or medications that predispose an individual to secondary osteoporosis (intestinal absorption problems, pulmonary or rheumatologic diseases requiring chronic corticosteroid medication use, or endocrine disorders affecting bone mineralization processes) are nonmodifiable or can be difficult to modify.

Table. Factors affecting bone strength

Screening recommendations

The NOF recently revised its recommendations for BMD screening using DXA measurement (see NOF Recommendations for bone mineral density testing).2 Routine screening is now recommended for women over age 65 and men over age 70.2 Screening for postmenopausal women and men ages 50 to 70 is recommended if they have clinical risks. Additionally, screening is recommended for perimenopausal women if they have a specific risk factor such as previous low-trauma fracture, low body weight, or are taking a medication known for increasing the risk of bone loss.

Identification of low bone mass or osteoporosis using T-scores reported by DXA measurement has been defined by the World Health Organization (WHO) (see WHO T-score interpretation).5 The T-score is reported as a standard deviation score that relates a patient's BMD to the normal BMD values of young adults of the same sex. The Z-score is a standard deviation score that identifies the patient's BMD as it relates to the BMD values of adults of the same age and sex. Z-scores are primarily used for evaluating bone density in children or young adults. T-scores are used for postmenopausal women and men over age 50.2 A careful history, physical exam, and appropriate lab evaluation are necessary prior to making a diagnosis of osteoporosis, even with DXA T-score results of -2.5 or lower; potentially treatable causes of secondary osteoporosis can be identified and managed.2

Clinical management for individuals with T-scores that indicate osteoporosis involve lifestyle changes to prevent further bone loss coupled with pharmacotherapy. Lifestyle changes are also appropriate for patients with T-scores in the osteopenic range (low bone mass is -1 to -2.5) and for preventing bone loss among those with normal BMD measurements.2,4 However, recommendations for initiating pharmacotherapy in patients with osteopenia have been less clear. While most agree that pharmacotherapy is warranted in patients with osteopenia if the T-score is -2.0 or if the patient has sustained a low-trauma fracture, there is little consensus on treatment plans for those with BMD in the -1 to -2 range or with risk factors other than low-trauma fracture.2

Table. WHO T-score interpretation

Fracture Risk Assessment Tool

Pharmacotherapy for osteopenia is used to prevent fractures as well as the development of osteoporosis. Recognizing the difficulty in measuring bone mass and bone quality accurately and determining best practices for clinical management for those with low bone mass, the WHO developed the Fracture Risk Assessment Tool (FRAX) to assess individual 10-year fracture risk.6,7 The algorithm, however, is applicable only for patients who have not received pharmacotherapy.2

The FRAX tool is accessible online and is available for multiple countries and in different languages (http://www.shef.ac.uk/FRAX/ ). The online tool incorporates 11 risk factors (See Risk factors incorporated in the WHO FRAX algorithm) and the femoral neck raw BMD value in g/cm2 to calculate the 10-year fracture risk probability.6 If the femoral neck BMD is not known, BMD of the total hip can be used instead; however, the use of nonhip BMD has not been validated and is not recommended.2 The site also offers downloadable charts for calculating fracture risks using body mass index (BMI) or BMD.

The FRAX algorithm identifies patients who might benefit from pharmacotherapy, and is most useful for recognizing those whose BMD levels fall under low bone mass, or osteopenic category. Since the 10-year fracture risk identified in the WHO technical report is nonspecific, economic modeling was used to determine the threshold for cost-effective, pharmacologic treatment of individuals in the United States.6,8 The U.S.–adapted algorithm was applied to determine applicability for pharmacotherapy decision making in various clinical scenarios based on the U.S. threshold recommendation.8,9 This analysis confirmed previously identified, cost-effective recommendations made by the NOF and the findings identified in the economic modeling analysis.8,10

Current NOF clinical recommendations for initiating pharmacotherapy now indicate treatment for men and postmenopausal women over age 50 who present with2:

Pharmacotherapeutic options, currently approved by the FDA include bisphosphonates, calcitonin, estrogen or hormone therapy, estrogen agonist/antagonist, and parathyroid hormone (PTH) medications (see Osteoporosis pharmacotherapy options). These medications fall into two categories: antiresorptive agents and anabolic agents. Bisphosphonates, calcitonin, estrogen/hormone therapy, and estrogen agonist/antagonists are antiresorptive agents that slow bone loss by interfering with osteoclast function to reduce the breakdown of old bone. This suppresses the process of bone resorption and allows osteoblasts, the cells responsible for building new bone, the opportunity to overcome osteoclast activity and increase bone formation. PTH is an anabolic agent and works with osteoblasts to increase new bone formation. A prescription medical food product, Fosteum, is also available. It is a combination of genistein (isoflavone purified from soy), zinc, and vitamin D, and has been shown to improve BMD (fracture data are not available).11

Bisphosphonates include alendronate (Fosamax and Fosamax Plus D), ibandronate (Boniva), risedronate (Actonel and Actonel with Calcium), and zoledronic acid (Reclast).12,13 Alendronate and risedronate are approved for postmenopausal osteoporosis prevention and treatment, glucocorticoid-induced osteoporosis treatment, and male osteoporosis treatment. Ibandronate is approved for postmenopausal osteoporosis prevention and treatment. Zoledronic acid is approved for postmenopausal osteoporosis treatment.

Oral bisphosphonates must be taken first thing in the morning on an empty stomach with 8 ounces of plain water. The patient must remain upright and not eat or drink anything for 30 minutes to 1 hour after ingesting the pill. This regimen has significantly reduced the potentially serious adverse reaction of esophageal erosion, which occurred when the medications were under study and first released for use. While this regimen can be challenging for some patients, the newer weekly and monthly dosing regimens are easier for patients to incorporate and follow.14,15 Some of the newer agents are available by I.V. administration (ibandronate and zoledronic acid); however, I.V. administration has difficulties as well. It requires an office visit every 3 months for ibandronate or annually for zoledronic acid, creating scheduling and time commitment problems for some patients. I.V. administration also requires a needlestick, which some are reluctant to accept due to discomfort.

Bisphosphonates are highly effective in reducing fracture rates, and the effects are maintained for many years following discontinuation. Alendronate reduces fractures at the spine, hip, and other sites by about 50% as compared with placebo.16,17 Risedronate reduces fracture rates at the spine, hip, and other sites by about 50% to 60%.18 Ibandronate has also been shown to have a high efficacy in reducing vertebral fractures, by approximately 50% to 60%.19,20 Ibandronate has not been shown to reduce hip or other site fractures. Zoledronic acid has a very high efficacy in reducing vertebral fractures (about 75%), and a more modest reduction of hip and all-site fractures of about 25% to 35%.21,22

While differences exist among the bisphosphonates for benefit at specific sites, lack of proven fracture reduction at a specific site does not necessarily mean that the medication is not effective in reducing fracture. Differences in research design, trial population, definitions used for fracture, and risk for fracture can affect trial outcomes and make comparisons across studies difficult. According to a large, observational research study, nonvertebral fracture risk is similar among patients taking alendronate, raloxifene, and risedronate.23 In this same study, fracture risk was a little higher among those taking calcitonin.

Because bisphosphonates are extremely effective in suppressing bone resorption, there are concerns that bone quality could be compromised. Some case reports identified patients who sustained fractures while taking alendronate, possibly due to oversuppression of bone turnover.24 Oversuppression of bone turnover may alter bone strength, creating brittle, breakable bone, sometimes called “frozen bone,” where little is happening at the cellular level. Drug holidays may allow normal bone turnover intermittently while on therapy, and the newer, less frequent dosing schedules may help reduce this issue.

Another concern is osteonecrosis of the jaw (ONJ), which is a very rare condition associated with high-dose I.V. bisphosphonate for the treatment of malignancies, reduction of bone pain, and malignancy-related hypercalcemia.25 ONJ occurs when bone tissue in the jaw is exposed for 3 months or more, and nonhealing lesions develop.26 Patients at risk include those with cancer who are taking high-dose I.V. bisphosphonates and have poor dental health, bony abnormalities in the mouth, gum injury, or are taking medications that interfere with healing. Occurrences of ONJ are rare, affecting 2% to 10% of patients taking high-dose I.V. bisphosphonates for bone-related cancers.27,28 Estimated occurrence among healthy patients who take bisphosphonates for osteoporosis prevention or treatment is even lower, ranging from 0.001% to 0.002%.29,30 ONJ is most likely to occur following an invasive dental procedure; patients taking a bisphosphonate should be counseled to advise their dentist of the drug prior to invasive dental procedures, as well as to adhere to a healthy dental hygiene regimen.26

Calcitonin (Miacalcin, Fortical) is FDA-approved for postmenopausal osteoporosis treatment, but is often used off-label as an analgesic agent for reduction of bone pain associated with vertebral compression fractures (VCF).31,32 Miacalcin can be administered by subcutaneous or I.M. injection, or as a nasal spray. Fortical is administered as a nasal spray.12,13 Nasal calcitonin reduces the risk of vertebral fractures by about 30% to 35% and is well tolerated. The most commonly reported adverse reaction is nasal irritation.32, 33

Hormone therapy

Estrogen and estrogen-plus-progesterone therapy have long been known to significantly increase BMD.32 Data from the Women's Health Initiative (WHI) study demonstrated a significant reduction in hip fracture of about 35% (all-site fracture reduction was about 25%) among women taking estrogen-plus-progesterone. The rates among women taking estrogen alone signified a 40% and 30% reduction in hip fractures and all-site fractures, respectively .34–36 This same trial identified increased risks for coronary heart disease, VTE events, stroke, and breast cancer, and reduced risk for colorectal cancer.34,36 The WHI was stopped early because overall risks outweighed the benefits. Following the release of the WHI data, there was great debate regarding the safety of estrogen and hormone therapy. Participants were asymptomatic postmenopausal women with an average age of 63. More recent studies have demonstrated that use of estrogen or estrogen-plus-progesterone at the time of transition to postmenopause is not associated with an increased risk for CVD and may actually be associated with a reduction of risk.37,38

Various forms of estrogen and estrogen-plus-progesterone are FDA-approved for osteoporosis prevention, including oral tablets; transdermal patches, creams, and gels; and injectables. In the wake of the WHI study, estrogen and estrogen-plus-progesterone use is now reserved for women with moderate-to-severe menopause-related symptoms and is not recommended for health promotion alone, such as preventing bone loss or coronary heart disease.32

While it was once thought that the beneficial effects of estrogen on bone were lost after treatment was stopped, a recent study indicated that estrogen therapy taken for as little as 2 to 3 years during the early postmenopausal period had beneficial effects on BMD and fracture risks 15 years after discontinuation.39

Estrogen agonist/antagonist

The only FDA-approved estrogen agonist/antagonist (EAA) for osteoporosis treatment is raloxifene (Evista). Raloxifene was categorized as a selective estrogen reuptake modulator until September 2007, when the FDA changed the name of this medication category to estrogen agonist/antagonist. Raloxifene is effective in reducing vertebral fractures by 30% to 50% and increases BMD by 2.1% to 2.4% at the hip and by 2.6% to 2.7% at the spine. Fracture risk at other sites was not reduced as compared with placebo.40 Raloxifene also reduces risk for breast cancer41 and was recently FDA- approved for breast cancer prevention.

Teriparatide (Forteo) is the only PTH medication currently FDA-approved for osteoporosis treatment. Teriparatide is highly effective in building bone and reducing fracture. A 20 mcg dose reduced fracture rates by about 65% at the lumbar spine and about 55% at nonvertebral sites. BMD also showed a significant increase—9% at the spine, 3% at the femoral neck, and 2% to 4% in the total body.42 Teriparatide is very costly (approximately $850 per month) and given by subcutaneous injection.12,13 Despite its high degree of efficacy, it is generally not used as a first-line therapy. Additionally, teriparatide cannot be used for lengthy periods of time; safe use has only been established for up to 2 years.12

Combining therapies may be necessary to improve bone density effectively. However, potential safety concerns and lack of solid supporting data limit this practice to those with very severe cases of osteoporosis. Treatment is usually initiated by an osteoporosis specialist. While some data are available, few report fracture rates with combined therapies, making evidence-based practice for combining agents difficult. Alendronate combined with estrogen is more effective in improving BMD than either therapy alone.43 Increased BMD lasted longer after discontinuation among those treated with both medications than with alendronate or estrogen alone.44 Risedronate combined with estrogen has been shown to increase BMD more than either therapy alone.45 Similarly, raloxifene combined with alendronate increased BMD more than either therapy alone.46 PTH in combination with estrogen has been shown in a small study to reduce vertebral fractures and increase BMD.47

Oversuppression of bone when combining pharmacotherapeutic agents is a concern. The goal for turnover suppression is 40% to 80%; it is a wide range because some patients respond well at the lower end and others require higher rates of suppression for positive BMD changes to be identified. Alendronate combined with estrogen can suppress bone turnover by up to 98%.48 Risedronate combined with estrogen can suppress bone turnover by up to 79%.45 Combining alendronate and raloxifene causes suppression of bone turnover that is greater than when either drug is used alone.46

Selecting a pharmacologic agent

Estrogen or hormone therapy is highly effective in preventing bone loss and is the first-line agent for use in women with moderate-to-severe menopause-related symptoms.32 Although a low-dose estrogen patch (Menostar), is FDA-approved for osteoporosis prevention, few clinicians currently prescribe estrogen for osteoporosis management unless a woman is experiencing menopause symptoms concurrently. Data reported in 2007 indicate that the low-dose estrogen patch is effective in reducing hot flashes.49 Other estrogen and estrogen-progestin options are effective in reducing bone loss while also managing hot flashes, vaginal atrophy, and other menopause symptoms, making them an excellent option for women who are experiencing such symptoms.

Raloxifene can be used if a woman has contraindications to using bisphosphonates (active, upper GI irritation or disease), does not tolerate a bisphosphonate, is at risk for breast cancer, or if the adverse reaction of hot flashes is not likely to cause or increase symptoms. Calcitonin is approved for postmenopausal osteoporosis treatment; however it is less effective than the bisphosphonates or raloxifene for reducing fractures.23 Calcitonin can be used for pain management following acute clinical VCF, to manage chronic bone pain due to VCFs alone, or with other agents, such as raloxifene.

Because of cost and the required daily injections for administration, PTH is reserved for use when first-line therapies fail. It is most effective when used in succession after bisphosphonate or raloxifene has been discontinued. One study indicated that efficacy was higher when PTH was used after risedronate than when it was used after alendronate.50 Additionally, a bisphosphonate or raloxifene can maintain and continue to improve BMD after a course of PTH has been completed.

Monitoring BMD

Monitoring BMD and response to therapy should include BMD testing. DXA should be completed every 1 to 2 years until bone values are stabilized, taking into account expected response and clinical necessity.2,32 Medicare covers serial DXA testing; however, local Medicare carriers set the frequency allowed in particular geographic locations.2

Changes in BMD values can be affected by many variables other than the patient's risk factors and medications, including the specific machine used, the skill of the technician in using the machine and positioning the patient, the site being measured, and the confidence intervals that are used.2 Because of these potential variables, changes in T-scores at the spine must differ by more than 2% to 4% and at the hip by more than 3% to 6% to be significant, and they may indicate a need to review or change treatment.2

Emerging treatments

Therapies under investigation for osteoporosis management include Preos, a new recombinant human parathyroid hormone (rh PTH 1–84), a new EAA medication (Bazedoxifene), osteoprotegerin, monoclonal antibodies, vitamin D analogues, and radionuclides.4,51,52 One monoclonal antibody, denosumab, is currently under FDA review.54 Isoflavone products are also being evaluated for efficacy as are new dosing regimens for existing medications. These new strategies will add even more options and necessitate careful decision-making to determine best practices for osteoporosis management plans.

Moving toward positive outcomes

Source: FRAX WHO risk assessment tool. http://www.shef.ac.uk/FRAX/ .

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