Vertebral Augmentation: The Comprehensive Guide to Vertebroplasty, Kyphoplasty, and Implant Augmentation

34 Treatment of Osteoporosis after Vertebral Augmentation

Amanda Schnell, Sarah Morgan, John W. Amburgy, James Mooney, D. Mitchell Self, and M. R. Chambers

Summary

Osteoporosis, a systemic disorder of altered bone strength, continues to be an under-recognized condition with an immense economic burden and public health impact, despite having a greater associated burden of disability than nearly all types of cancer. As the result of the increasing average age of the population in the United States, the cost of care of osteoporosis is expected to rise significantly to $25.3 billion by 2025. Although diagnosis and treatment results in considerable health care expenditures, the failure to diagnose is even more costly. For many patients, the diagnosis of a vertebral compression fracture (VCF) is often the first indication of osteoporosis. It is also an opportunity to provide the patient with appropriate treatment and education about the disease. Patients who experience VCFs are often referred to an osteoporosis specialist following vertebral augmentation. Fracture liaison services (FLSs) are designed to assist with the transition and continuation of osteoporosis care from the inpatient to outpatient setting and are tasked with following and treating patients with osteoporosis and/or osteoporotic fractures. Essential to the success of an FLS or the clinician treating the disease process of osteoporosis after the fragility fracture has been treated is enhanced communication with the health care team providing these treatment services. Using appropriate clinical care pathways based on evidence-based guidelines is also important to ensure the correct approach to treatment. This can be combined with optimal patient education and tracking of patient outcomes in a continued effort to provide the best quality of care.

Keywords: osteoporosis, vertebral compression fracture (VCF), fragility fracture, fracture liaison service, FRAX, bone mineral density, T-score, vertebral fracture assessment, dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS)

34.1 Introduction

For many patients, the diagnosis of a vertebral compression fracture (VCF) is often the first indication of osteoporosis. It is also an opportunity to provide patients with appropriate treatment and education about the disease.

Osteoporosis, a systemic disorder of altered bone strength, continues to be an under-recognized condition, despite having a greater associated burden of disability (e.g., loss of work days, pain) than all sites of cancer, with the exception of lung cancer. Despite available screening tools, advances in pharmacologic therapy, and widespread education regarding exercise and adequate nutrient intake, the diagnosis and treatment rates of osteoporosis in the United States fall well below standards set by the National Osteoporosis Foundation (NOF) guidelines.¹^,²

The year following an initial fragility fracture (which is defined as any fracture resulting from a fall from standing height or less) holds the greatest risk for subsequent fractures. One-fifth to nearly one-half of patients experience another fracture within the year after the initial fragility fracture.³^–⁵ Unfortunately, only one-fourth of patients who sustain a fragility fracture (including a vertebral fracture) are formally diagnosed with osteoporosis within the year, despite the fact that sustaining a fragility fracture is a defining event of osteoporosis⁶^–⁸ and only one-fourth of patients who experience an osteoporotic fracture are on pharmacologic osteoporosis therapy at 1 year, putting them at higher risk for additional fractures.⁹^,¹⁰

34.2 Etiology and Epidemiology

As osteoporosis is a bone disorder characterized by decreased bone strength, it increases the risk of fracture. Bone strength is composed primarily of two components: bone density and bone quality. Bone density is determined by peak bone mass and the rate of subsequent bone loss, and is expressed as grams of mineral per area or volume. Bone quality refers to architecture, turnover, damage accumulation (e.g., micro-fractures) and the degree of mineralization.¹¹ Osteoporosis results from an imbalance between bone formation and bone loss, with formation being less than loss as well as diminished bone quality. When a failure-inducing force is applied to osteoporotic bone, which can even be normal force on a weakened bone, a fracture occurs.¹¹

Osteoporosis occurs in both sexes, but is more often recognized and diagnosed in women following menopause (▶Fig. 34.1).¹¹ Both men and women have an age-related decline in bone mineral density (BMD) in midlife due to increased bone resorption as compared to bone formation, though women experience a more rapid bone loss in the early years after menopause.¹¹ Fractures in men typically occur about a decade later than in women. Peak bone mass is not completed until age 30, after linear bone growth has ceased. Therefore, bone mass attained early in life may be the most important determinant of skeletal health later in life.¹¹^,¹²

Peak bone mass may be affected by genetic and lifestyle factors including nutrition (lifetime calcium and vitamin D intake), physical activity, smoking, alcohol, eating disorders, autoimmune diseases, glucocorticoid medications, and endocrine disorders that affect sex steroids.¹² Characteristics associated with low bone mass later in life include female sex, increased age, estrogen deficiency, white race, low weight and body mass index (BMI), and family history of prior fracture.¹¹ The list of possible secondary causes is lengthy and includes endocrine and metabolic conditions, nutritional or collagen metabolism disorders, and drug side effects. Conditions that may contribute to low bone mass include genetic diseases, hypogonadal states, malabsorption disorders, celiac disease, Crohn disease and gastric bypass, multiple myeloma, malignancy, rheumatologic and autoimmune diseases, end-stage renal disease, and post-organ transplantation status.¹³

Fig. 34.1 (a) Compression fractures of thoracic vertebrae lead to loss of vertebral body height and progressive thoracic kyphosis. The lower ribs eventually rest on iliac crests, and downward pressure on viscera causes abdominal distention. (Source: Netter 1987. Netter Illustrations reproduced with permission from Icon Learning Systems, a division of MediMedia, USA, Inc. All rights reserved.) (b) Medical illustration showing normal bone (left) with greater thickness of the cancellous bone, less porous bone architecture, and more bridging plates as compared with the osteoporotic bone (right) with less bone, greater porosity, and less bridging plates.

34.3 Economic Burden

Osteoporosis and associated osteoporotic fractures have a profound effect on individual morbidity and mortality and are exceedingly common. The NOF estimates that 10.2 million Americans have osteoporosis and that an additional 43.4 million individuals have low bone mass.

There were an estimated 2 million fractures attributable to osteoporosis in 2005, with 27% of the fractures occurring at vertebral sites.¹⁴ Not only are the fractures quite common, the economic burden and public health impact are immense. It is estimated that over 400,000 hospital admissions, 2.5 million medical office visits, and 180,000 nursing home admissions were related to osteoporotic fractures in 2004.¹⁵ Hospital costs for a single inpatient admission related to vertebral fracture may total approximately $12,000.¹⁶

Vertebral fractures are roughly twice as common as a hip fracture and are the most common type of osteoporotic fracture. Vertebral insufficiency fractures indicate a high risk for future fractures regardless of whether or not the bone density testing (T-score) meets the threshold for osteoporosis.¹⁴

Significant costs related to fracture care are incurred by inpatient care, long-term care facilities, and outpatient care.¹⁷ In the year following a fracture, medical and hospitalization costs were 1.6 to 6.2 higher than prefracture costs and 2.2 to 3.5 times higher than those for age-matched controls with costs totaling up to $71,000 for a hip fracture and up to $68,000 for a vertebral fracture.¹⁸ Medicare pays for approximately 80% of these fragility fracture costs.¹⁷ Given the recent prominent increase in the age of the population, the cost of care of osteoporosis is expected to rise to $25.3 billion by 2025.¹⁷ In addition to the medical costs, indirect costs are also prominent, including the price of reduced productivity due to disability and reduced workforce participation, and patients are also at substantial risk of premature death.¹⁵

Failure to detect clinical osteoporosis when it is present likely contributes to the current lack of awareness of the consequences of the disease by both clinicians and patients. This impacts the reimbursement strategies of payers, influences policy makers in the public health sector by underestimating the number of those at increased fracture risk, and affects the design of clinical trials of new agents to reduce fracture.¹⁹

34.4 Presentation and Diagnosis

Screening at-risk populations for osteoporosis is essential. In the case of a patient presenting after vertebral augmentation, the diagnosis of osteoporosis is a foregone conclusion, provided the vertebral fracture was a fragility fracture. Many vertebral fractures, however, are silent and often go undiagnosed.

Based on guidelines from the World Health Organization (WHO) and the NOF, the diagnosis of osteoporosis may be made by meeting any one of these criteria: the presence of a fragility fracture in the absence of other metabolic bone disorders or high velocity trauma; a T-score of −2.5 or lower on DXA imaging, even in the absence of a prevalent fracture and in patients with osteopenia and an increased fracture risk, using Fracture Risk Assessment Algorithm (FRAX) country-specific thresholds.¹³^,¹⁴^,¹⁹^,²⁰ (See “Fracture Risk Assessment Algorithm (FRAX below.)

Since approximately 30% of osteoporosis cases in postmenopausal women are believed to be due to a secondary cause, a thorough history, physical exam, and laboratory testing could be performed to identify secondary causes.¹^,¹⁴^,¹⁹ Laboratory testing may include:

• Complete blood count (CBC).

• Serum chemistries (calcium, phosphorus, renal, and liver function tests).

• Thyroid-stimulating hormone (TSH).

• 25-Hydroxy vitamin D3 (25(OH)D.

• Intact parathyroid hormone (PTH).

• Serum/urine protein electrophoresis.

• Serum/urine immunofixation electrophoresis.

• Serum-free light chains.

• Tissue transglutaminase antibodies and total IgA.

• Urine calcium/creatinine ratio +/− 24-hour urine for calcium excretion (including urine sodium and creatinine to assess the adequacy of collection).

• Bone turnover markers (BTMs) in select patients:

– Bone resorption markers: Collagen cross-linked N-telopeptide (NTX), collagen type 1 c-telopeptide (CTX).

– Anabolic markers: Procollagen 1 propeptide (P1NP), bone-specific alkaline phosphatase (BSAP).

In patients with clinical or biochemical evidence of malabsorption, celiac antibodies should be obtained. Serum and urine protein electrophoresis may be obtained if there is a suspicion for multiple myeloma (e.g., non-PTH-mediated hypercalcemia).¹⁴ Also in select cases, urine-free cortisol, testosterone, follicle-stimulating hormone (FSH), and tryptase levels may be indicated. It should be noted that the 24-hour urine calcium collection must occur after the patient is vitamin D replete and has been on a reasonable calcium intake (1,000–1,200 mg/day) for at least 2 weeks.

34.5 Dual-Energy X-ray Absorptiometry

Dual-energy X-ray absorptiometry (DXA) imaging can provide valuable information in the diagnosis of osteopenia and osteoporosis and in the monitoring of BMD. In general, DXA imaging should be ordered for screening in all women age ≥ 65 years of age, men age ≥ 70, postmenopausal women and men age 50–69 based on risk factor profile, and postmenopausal women and men age ≥ 50 who have had an adult age fracture.¹³

BMD is measured with DXA of the lumbar spine (on the anteroposterior view), femoral neck, and total hip. The distal one-third of the radius should be scanned in individuals with hyperparathyroidism, in those who do not have a valid spine or hip site, or in individuals whose weight exceeds the maximum limit of the table.²⁰ Area BMD is expressed in g/cm² and as a relationship to two norms: the BMD of an age-, sex-, and ethnicity-matched reference population (Z-score) or a young-adult reference population of the same sex (T-score). The difference between the patient’s BMD and the mean BMD of the reference population, divided by the standard deviation (SD) of the reference population, is used to calculate Z- and T-scores.¹³ In postmenopausal women and men age 50 and older, the WHO diagnostic T-score criteria are applied. In premenopausal women, men less than 50 years of age, and in children, the ethnic or race-adjusted Z-scores should be used.²¹ In premenopausal women and men less than age 50, a Z-score ≤ −2.0 is BMD below the expected range for age and a Z-score > −2.0 is BMD within the expected range for age (see ▶Fig. 34.2).

The WHO criteria for the diagnosis of osteoporosis based on BMD (T-scores) using DXA measurement are as follows:

• Normal: T-score ≥ −1.0 SD.

• Low bone mass: −2.5 SD < T-score < −1.0 SD.

• Osteoporosis: T-score ≤−2.5 SD.

• Severe osteoporosis: T-score ≤−2.5 plus one or more fragility fractures.²²

Along with traditional DXA imaging, other DXA-based tools have been developed to assist the clinician in the evaluation and prediction of risk of fracture for individual patients. These tools include vertebral fracture assessment (VFA), trabecular bone score (TBS), extended femur scans to detect incomplete atypical femoral fractures, vertebral radiographs, and FRAX.

34.6 Vertebral Fracture Assessment

Vertebral fracture assessment (VFA) is a measurement tool that uses lateral images obtained by DXA to identify asymptomatic vertebral fractures. VFA should be performed if the results may alter the decision to treat or not to treat, change the drug selected for treatment, or affect the follow-up of the patient.²³ Three patterns of vertebral deformation have been described in VFA: wedge, biconcave, and crush.²⁴ Up to 25% of patients over age 60 who are being evaluated for osteoporosis have been found to have vertebral fractures with only 11% of those patients reporting a history of vertebral fracture.²⁵ Using VFA to identify individuals with asymptomatic vertebral fractures as part of a comprehensive risk assessment may aid in clinical decision-making.²³^,²⁶ Detection of vertebral fractures has traditionally relied on standard radiographs of the spine, which are associated with cost and radiation exposure and require a separate visit. Therefore, radiographs are usually not obtained in the standard evaluation of patients with osteoporosis.²⁵ Using DXA technology, radiation exposure and cost can be lessened, and vertebral anatomic information is available to the physician at the patient’s clinic visit.²⁵

34.7 Radiographs

In addition to VFA, vertebral imaging with AP, lateral, and in some cases oblique and spot views is indicated in all women age ≥ 70, all men age ≥ 80 if BMD is ≤ −1.0 at the spine, total hip, or femoral neck, in women age 65 to 69 and men age 70 to 79 if BMD T-score is ≤ −1.5 at the spine, total hip, or femoral neck.¹³^,²³ Vertebral imaging is also indicated in postmenopausal women and men age ≥ 50 with the following specific risk factors: low-trauma fracture during adulthood (age 50 and older), historical height loss (difference between the current height and peak height at age 20) of 1.5 inches (4 cm) or more, prospective height loss (difference between the current height and a previously documented height measurement) of 0.8 inches (2 cm) or more, or recent or ongoing long-term glucocorticoid treatment.¹³^,²³

Fig. 34.2 DXA imaging of the lumbar spine including a lateral (a) and an anteroposterior view (b) and with T- and Z-scores representing the comparison to young healthy adults and matched controls, respectively (c).

34.8 Trabecular Bone Score

Trabecular bone score (TBS) is an analytical tool that uses measurements on the lumbar spine DXA to capture information related to trabecular microarchitecture. The TBS decreases with age and reflects qualitative aspects of skeletal structure that complements the quantitative measurement of BMD.²⁷ Low TBS is consistently associated with an increase in fractures and is partly independent of both clinical risk factors and BMD at the lumbar spine and proximal femur.²⁸ Therefore, this technique may aid in clinical decision-making regarding the need for pharmacologic therapy or the type of medication used. More studies are needed to determine the optimal clinical use of TBS.

Extended femur scanning by DXA is a screening tool that is used to detect incomplete atypical femur fractures in patients on antiresorptive therapy. Though individuals with atypical femur fractures may present with prodromal groin or thigh pain, others are asymptomatic.²⁹^,³⁰ This tool may be considered in individuals who have previously sustained an atypical femoral fracture, bisphosphonate users who report pain in the hips, groin, or upper legs, and in individuals who have taken antiresorptive therapy for more than five years or have other risk factors for developing an atypical femoral fracture.²⁹

34.9 Fracture Risk Assessment Algorithm (FRAX)

FRAX is a risk assessment tool that can be used to estimate the 10-year fracture risk with or without femoral neck BMD. FRAX is a country- and ethnicity-specific fracture risk assessment that combines BMD at the femoral neck (or total hip) with a group of well-validated and weighted clinical risk factors for fracture that are largely independent of BMD.³¹ Age and mortality are taken into account, which are unique benefits of this algorithm. Other factors in the algorithm include gender, height, weight, BMI, personal fracture history, parental history of hip fracture, glucocorticoid use, rheumatoid arthritis, and the current use of tobacco and excessive alcohol intake. Treatment is indicated or suggested when the 10-year probability of a major osteoporotic fracture (spine, forearm, hip, or shoulder) is ≥ 20% or the 10-year probability of hip fracture is ≥ 3%. FRAX does have limitations and is most appropriate in patients with low femoral neck BMD. Using FRAX in patients with low BMD at the lumbar spine but a relatively normal BMD at the femoral neck will underestimate fracture risk in these individuals. Furthermore, it may also underestimate fracture risk in patients with recent fractures, multiple osteoporosis-related fractures, and those at increased risk for falling.¹³ FRAX (▶Fig. 34.3) can be accessed at: https://www.sheffield.ac.uk/FRAX/index.aspx.

Fig. 34.3 FRAX website. (Reproduced with permission of © Centre for Metabolic Bone Diseases, University of Sheffield, UK.)

34.10 Treatment

Treatment of osteoporosis is indicated in any patient with a low velocity fracture or a hip or vertebral fracture (regardless of BMD).¹³^,²⁰^,²¹^,³² Pharmacological osteoporosis therapy should be considered in any patient with a T-score of ≤ −2.5 at the femoral neck, total hip, lumbar spine, or distal one-third of the radius or one with a T-score between −1.0 and −2.5 (osteopenia) and increased fracture risk by FRAX (10-year hip fracture risk of ≥ 3% or a 10-year major osteoporosis-related fracture probability ≥ 20%).¹³^,²⁰ Pharmacological therapy is also indicated in patients who are at moderate-to-high risk of fracture on glucocorticoid therapy.³³

34.10.1 Referral

A patient who experiences a fragility fracture is either treated by the physician treating the fracture or the patient may be referred to an osteoporosis specialist following definitive treatment of the fracture. The referral should be prompt, as there is most often a significant risk of additional fracture in the first few months or first year following the incident fracture. The largest vertebral augmentation trial ever published reported a very high rate of additional vertebral fracture of 47.6% during the first year after the initial VCF.⁵ Many other patients referred to a specialized osteoporosis center by general medicine specialties may present with an asymptomatic diagnosis of osteoporosis based on DXA imaging. Referral to an osteoporosis specialist is indicated in the following situations:²⁰

• A patient with normal BMD who sustains a fracture without major trauma (e.g., a fragility fracture).

• A patient who presents with recurrent fractures or has continued bone loss while on pharmacologic osteoporosis therapy without obvious treatable causes of bone loss.

• When osteoporosis is unexpectedly severe, has unusual features, or less common secondary conditions (e.g., hyperthyroidism, hyperparathyroidism, hypercalciuria, or elevated prolactin) are identified.

• When a patient has a condition that complicates management (e.g., chronic kidney disease: glomerular filtration rate [GFR] < 35, hyperparathyroidism, or malabsorption).

34.10.2 Fracture Liaison Service

In 2011, the International Osteoporosis Foundation (IOF) Committee of Scientific Advisors Fracture Working Group published a report that described a “care gap in secondary prevention” of osteoporosis and called for expansion of existing clinical systems aimed at ensuring appropriate management of patients following fracture.³⁴ The following year, the American Society of Bone and Mineral Research Task Force report on secondary fracture prevention noted few such systems in place and presented “medical and ethical rationale” for cost-effective interventions to treat and prevent fragility fractures. The authors highlighted strategies and barriers to implementation as well as the “ethical imperatives for providing osteoporosis management … and research questions that remain outstanding.”³⁵

To facilitate referral of patients seen and treated for hip or vertebral fractures and to minimize the risk of subsequent fractures, a fracture liaison service (FLS) led by a dedicated physician or advanced practice provider coordinator is optimal. FLSs are designed to assist with the transition and continuation of osteoporosis care from the inpatient to outpatient setting—in particular, following treatment of an osteoporotic fracture. Communication with primary care physicians and the health care team as well as tracking of patient care and outcomes is essential to the service. FLS model should include the following key elements:³⁶

• Enhanced communication between health care providers.

• Identification of patients diagnosed with a fragility fracture in a health care system.

• Individualized evaluation with fracture risk modification treatment and management by a bone health expert.

• Clinical pathways formulated based on evidence-based guidelines.

• Patient education.

• BMD testing.

• Bone health follow-up and participation in an outcomes registry.

The FLS model has been shown to be cost saving and to promote alignment of the objectives of policy makers, health care professionals, and patients. Successful transformation of care relies upon collaboration among all participants in the multidisciplinary team that cares for fragility fracture patients.³⁷

34.10.3 Nonpharmacological Treatment

Pharmacologic therapy and surgical interventions play an integral role in the treatment of osteoporosis, but nonpharmacological treatments are also important and may help prevent future fracture. Most osteoporotic fractures occur due to falls; therefore, clinicians need to assess risk factors and discuss fall prevention measures with patients. Major risk factors of falls include a personal history of falling, muscle weakness, selected medications, abnormal balance, and visual deficits, and dehydration.³⁸ The Centers for Disease Control and Prevention (CDC) has developed a fall prevention program, named Stopping Elderly Accidents, Deaths & Injuries (STEADI), based on the American and British Geriatrics Societies’ clinical guidelines. These recommendations consist of three main elements: screen, assess, and intervene.³⁹ Patient brochures and questionnaires can easily be implemented into the previsit or clinic visit and accessed at https://www.cdc.gov/steadi/index.html.

Calcium and Vitamin D

Calcium is a building block of bone and is necessary for the development of peak bone mass and maintenance of bone health. Vitamin D plays a key role in the absorption of calcium. Individuals should be advised of the recommended daily dietary intake of calcium and vitamin D as it is a safe and inexpensive way to help reduce fracture risk.¹³^,⁴⁰ If adequate dietary intake cannot be achieved, supplementation should be initiated. The Institute of Medicine (IOM) recommends that men age 50 to 70 consume 1,000 mg/day of calcium and that women age 51 and older and men age 71 and older consume 1,200 mg/day of calcium. The NOF recommends adults age 50 and older intake 800 to 1,000 international units (IU) of vitamin D per day. The IOM recommends adults age less than 70 intake 600 IU/day and adults age 71 and older intake 800 IU/day of vitamin D.⁴¹ It should also be kept in mind that vitamin D deficiency is exceedingly common and additional supplementation may be necessary to bring the vitamin D level back to a normal range. Serum 25(OH) D levels should be obtained in patients with osteoporosis or fracture. Serum 1,25(OH)2D should not be measured as it provides no information about vitamin D status and is often normal or elevated due to secondary hyperparathyroidism associated with vitamin D deficiency.⁴² There is general agreement that a level of 25(OH)D of < 20 ng/mL is considered to be vitamin D deficiency whereas a level of 25(OH)D of 21 to 29 ng/mL is considered to be insufficient. The goal should be to maintain the level of 25(OH) D at > 30 ng/mL to take full advantage of all the health benefits that vitamin D provides.⁴² Levels higher than 70 ng/mL probably provide no additional benefit. There are experts who suggest that there are no detrimental effects of levels of vitamin D higher than 70 ng/mL, but this recommendation is only for short-term use and not intended to be applied for chronic long-term dosing of vitamin D.

Supplementation should be initiated to bring the serum 25(OH) D level optimally between 40 and 50 ng/mL and a maintenance dose continued to maintain this level. Individuals with vitamin D deficiency may be treated with 50,000 IU of vitamin D3 weekly or the equivalent daily dose (7,000 IU vitamin D3) for 8 to 12 weeks to achieve a 25(OH) D level of at least 30 ng/mL but ideally 40 to 50 ng/mL. Replacement should be followed by maintenance dosing of 1,500 to 2,000 IU/day to keep 25(OH) D level between 40 and 50 ng/mL.⁴⁰^,⁴¹

An alternate dosing regimen that may be used in patients who have had fragility fractures and are being placed on a limited duration of antiosteoporosis medication (i.e., anabolic bone agents) is dosing the vitamin D3 supplementation between 2,000 and 5,000 IUs and giving it along with calcium and the antiosteoporotic medication. In general, 100 IU of vitamin D per day can raise the vitamin D blood test only 1 ng/mL after 2 to 3 months so 1,000 IU per day increases vitamin D blood levels 10 ng/mL and 2,000 IU per day increases vitamin D blood levels 20 ng/mL.⁴³ This assumed a linear relationship between vitamin D absorption and distribution which is very often not the case and the oral vitamin D bioavailability is dietary and patient dependent. Individuals with poor bowel absorption or an inflamed bowel, or who are obese, can require much more vitamin D3. Given these dosing and absorption factors, an individual who has suffered an osteoporotic fracture can be placed on a dose of vitamin D3 of 2,000 to 5,000 IU daily or 50,000 IU weekly. Based on optimal absorption, this would increase the individual’s vitamin D3 levels up to 50 ng/mL. So if the individual is vitamin D deficient, this amount would increase their level up to, or very close to, an optimal level. If they are not vitamin D deficient it would increase it up to levels that, if taken for a limited time period, won’t increase the level of vitamin D to harmful levels. Based on risk assessment, a safe upper intake level of 10,000 IU per day in healthy adult has been previously suggested, so a dose of 5,000 IU is thought to be safe for a limited amount of time such as the 18 months to 2-year time period it takes for the treatment with anabolic bone agents.⁴⁴^,⁴⁵

34.10.4 Pharmacological Treatment

As an adjuvant to surgical intervention, pharmacological treatment of osteoporosis reduces risk of future fracture. Current FDA-approved pharmacologic options for osteoporosis treatment are bisphosphonates, calcitonin, estrogen agonists/antagonists, estrogens/hormone replacement therapy, tissue-selective estrogen complexes, parathyroid hormone 1–34 and PTH-rP(teriparatide and abaloparatide), and receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor (denosumab). Commonly used medications for pharmacologic osteoporosis treatment with indications, risks and benefits, efficacy on vertebral or nonvertebral sites, and use in special populations are summarized and listed in ▶Table 34.1.

Calcitonin is a peptide that is analogous to human calcitonin. It is indicated in use in women who have been postmenopausal for at least 5 years.¹³ It has been shown to reduce vertebral fracture occurrence by about 30% in those with prior vertebral fractures, but has not been shown to reduce the risk of nonvertebral fractures.⁴⁶^,⁴⁷ It is no longer approved in Europe for treatment of osteoporosis.

Estrogens (including bazedoxifene-conjugated equine estrogen) are FDA approved for the prevention of osteoporosis. The Women’s Health Initiative (WHI) found that 5 years of hormone replacement therapy reduced risk of clinical vertebral fractures and hip fractures by 34% and other osteoporotic fractures by 23%.⁴⁸ Bazedoxifene-conjugated equine estrogen increased mean lumbar spine BMD at 12 months compared to placebo in women who had been postmenopausal between 1 and 5 years.⁴⁹^,⁵⁰ However, drug safety issues exist with hormone replacement therapy, including increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis.⁴⁸ Rapid bone loss may also occur when estrogen therapy is discontinued. The FDA now recommends that approved nonestrogen treatment should be carefully considered first if using estrogen solely for prevention of osteoporosis.¹³

Raloxifene is approved by the FDA for both prevention and treatment of osteoporosis in postmenopausal women. It is indicated for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and has been shown to reduce risk of vertebral fractures by about 30% in patients with a prior vertebral fracture and by about 55% in patients without a prior vertebral fracture over 3 years.⁵¹ Raloxifene increases the risk of venous thromboembolism.

Bisphosphonates are FDA approved for treatment and prevention of osteoporosis in postmenopausal women, men, and for glucocorticoid-induced osteoporosis prevention. Oral bisphosphonates include alendronate, risedronate, and ibandronate. Zolendronic acid is administered as an intravenous infusion. All bisphosphonates have been shown to reduce the risk of vertebral fractures and all but ibandronate have shown to reduce risk of nonvertebral and hip fractures. Alendronate reduced the incidence of vertebral fractures by 48%, ibandronate by 50%, risedronate by 41 to 49%, and zolendronic acid by 70% over 3 years.⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶ Vitamin D (25-OH) should be obtained before starting bisphosphonate therapy, as symptomatic hypocalcemia can develop in patients with low levels of 25-OH vitamin D who receive concomitant therapy with bisphosphonates.⁵⁷ Adverse effects of bisphosphonates include esophagitis (oral administration), an acute phase reaction (IV administration), musculoskeletal symptoms, osteonecrosis of the jaw (ONJ), and atypical femur fracture.⁵⁸ It should be emphasized that ONJ is an unusual complication of bisphosphonate therapy and the American Dental Association has published guidelines stating that the benefits of antiresorptive therapy outweigh the low risk of developing ONJ.⁵⁹

Denosumab is a receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor and is FDA approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture and for treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture.⁶⁰ It may also be used in men and in patients with glucocorticoid-induced osteoporosis. Denosumab has been shown to reduce incidence of vertebral fractures by about 68%, hip fractures by about 40%, and nonvertebral fractures by about 20% over 3 years.⁶¹ Adverse effects include hypocalcemia, increased risk of serious skin infections, rebound effect predisposing to multiple vertebral fractures, ONJ, and atypical femur fractures.¹³^,⁵⁷

Teriparatide and abaloparatide are parathyroid hormone analogs that are FDA approved for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture and for treatment in men and women at high risk of fracture with osteoporosis associated with sustained systemic glucocorticoid therapy.⁶² Treatment with teriparatide has been shown to reduce risk of vertebral fractures by about 65% and nonvertebral fragility fractures by about 53% in patients with osteoporosis, after an average of 18 months of therapy.⁶³ Treatment with abaloparatide has been shown to decrease the risk of vertebral fractures by about 86% and nonvertebral fragility fractures by 43% in osteoporotic patients after an average of 18 months of therapy.⁶⁴ In addition to this powerful fracture reduction, the anabolic bone agents can produce a prominent increase in the patients’ BMD by approximately 12% after a full course of therapy.⁶³

Each of the different classes of antiosteoporotic medications have their own effect on bone turnover with the bisphosphonates and RANK ligand inhibitors slowing bone turnover down sometimes up to 70% in just a few days after starting the medication.⁶⁵ The estrogens and estrogen receptor modulator medications have the effect of restoring the bone turnover to premenopausal levels in postmenopausal females, and the anabolic bone agents speed up bone turnover. Bone turnover can be assessed by evaluating the BTMs such as procollagen type 1 N-terminal propeptide (a marker of skeletal bone formation) and carboxy-terminal crosslinking telopeptide of collagen type 1 (a marker of bone resorption). Although it is not necessary to measure BTMs while using antiosteoporotic agents, they can be effective for assessing patient compliance and therapy efficacy. Significant reductions in BTMs are typically seen with antiresorptive therapy and can be associated with fracture reduction whereas significant increases indicate good response to anabolic therapy.²⁰

Given the prominent risk reduction in vertebral and nonvertebral fractures, anabolic bone therapy should be the mainstay in treating patients with vertebral fractures. Anabolic agents have been found to reduce the risk of additional vertebral fractures more than any of the antiresorptive medications and are able to produce prominent increases in BMD in a relatively short period of time. Anabolic agents also increase bone turnover which is optimal in patients after having had a major fragility fracture.

It has been suggested that in treatment of naïve patients, initiation of anabolic therapy should be first-line treatment as the substantial BMD increases in the hip and spine are blunted if an antiresorptive agent is given first, followed by the anabolic agent.⁶⁶ There is also a risk of rebound effect on patients stopping denosumab if this medication is used first. This rebound effect may result in the occurrence of multiple vertebral fractures and the progressive or transient bone loss can continue in spite of the introduction of an anabolic bone agent, whereas switching from an anabolic bone agent to denosumab results in the continued increase in BMD.⁶⁷ Cosman et al concluded in their “Treatment sequence matters” manuscript that the common practice of changing to an anabolic bone agent only after patients have had an inadequate response to antiresorptives is not the optimal utilization of anabolic treatment and may result in transient loss of hip BMD and strength.⁶⁶ Given the importance of treatment sequence for clinical outcome optimization for patients who need an anabolic bone agent, this medication should be used instead of an antiresorptive medication to potentially avoid decreasing the efficacy of the anabolic agent.

If anabolic bone agents are used initially and the subsequent medication is an antiresorptive, it has been shown that it is possible to not only continue to increase the BMD but also to propagate the vertebral and nonvertebral fracture reduction.⁶⁸ This is important as antiresorptive therapy is optimal to prevent the immediate loss of bone density upon the cessation of the anabolic bone agent. Cosman et al in the ACTIVExtend trial used 2 years of alendronate following 18 months of abaloparatide and found that during the extension the relative risk reduction for vertebral and nonvertebral fractures was maintained, which suggests that the advantageous effects of the anabolic bone agent abaloparatide was still present when following this treatment with alendronate. Additionally, they concluded that there appears to be a cumulative benefit favoring abaloparatide and subsequent alendronate than just alendronate alone.

In addition to improving the clinical outcomes by utilizing the optimal medication treatment sequence, this approach may also improve the cost effectiveness of the therapy. In a Markov cohort model, O’Hanlon et al estimated that during a period of 1.5 years, an anabolic bone agent (abaloparatide) can reduce fractures and provide improvements in quality adjusted life years (QALYs) and produce a cost saving of $17,000,000 per 10,000 patients treated.⁶⁹ Some studies have presented data indicating that in postmenopausal women at high risk for fractures, abaloparatide followed by alendronate leads to improved health outcomes by lowering the number of fractures and lower health care costs than using the same medications for treatment but starting with alendronate.⁷⁰ The authors measured the lifetime costs and number of fractures and calculated the QALYs and incremental cost-effectiveness ratio (ICER) when treating women 70 years of age with a T-score ≤−3.5.

It should be noted that a black box warning is present on both anabolic bone agents, stating that patients may be at an increased risk of osteosarcoma as there is an increase in osteosarcoma in rats treated with these medications. Despite this, there has been no demonstrable increased rate of osteosarcoma in patients treated with anabolic bone agents for more than a decade and a half. The treatment duration is recommended not to exceed 18 to 24 months and, as mentioned above, follow-up therapy with an antiresorptive agent, usually a bisphosphonate is also advised.¹³

A summary of the American Association of Clinical Endocrinologists/American College of Endocrinology guidelines for treatment of osteoporosis can be found at https://www.aace.com/files/final-algorithm.pdf.

34.11 Treatment of the Osteoporosis by the Physician Treating the Fracture

Although follow-up with an FLS is effective in treating patients after suffering a fragility fracture, the most optimal method of treatment of the underlying osteoporosis is by the provider treating the fracture. Prompt treatment of the decreased BMD is necessary because additional fractures typically occur soon after the incident fracture most commonly in the first year so the sooner the osteoporosis is treated the better.⁷¹ In fact the largest vertebral augmentation trial to date, “Prospective and multicenter evaluation of outcomes for quality of life and activities of daily living for balloon kyphoplasty in the treatment of vertebral compression fractures: the EVOLVE trial”, reported that in typical Medicare patients after undergoing kyphoplasty the rate of additional or adjacent-level vertebral fracture was 47.6% in the first year after the fracture.⁵ The most optimal way to control prompt treatment of the patient is to discuss the follow-up treatment at the time of the fracture treatment and then commence the antiosteoporotic therapy at the time of the first follow-up. This allows treatment initiation usually at approximately 2 weeks following the initial fracture fixation. Busy practices often hesitate to assume the responsibility of treating the underlying osteoporosis due to concerns that this will create extra work in an already busy practice, but given the fact that treating the underlying disorder can improve the immediate short-term and long-term outcomes of the fracture treatment, this process is essential for those practices that are interested in a sustainable and ideal treatment regimen. ▶Table 34.2 outlines a streamlined follow-up that may be incorporated for treating osteoporosis after the patient’s first vertebral fragility fracture. This involves obtaining typical preoperative laboratory assessment including a complete blood count (CBC) and complete blood chemistry (i.e., Chem-20). Provided the laboratory values including the patients renal function, calcium level, and alkaline phosphatase are normal and there was no suspicion of additional pathologic process on the imaging evaluation (i.e., metastatic disease or multiple myeloma detected on the imaging studies) or the biopsy obtained during fracture fixation, the treatment may proceed as outlined in ▶Table 34.2. The patient receives injection training at the time of the first visit as anabolic agents are both currently only available in an injectable form and these agents are used in the vast majority of patient with fragility fractures. The DXA scan is used not to diagnose osteoporosis (which is already apparent from the clinical history of a low-velocity injury producing a fracture) but performed mostly to monitor the patients’ BMD response to therapy. We have found that home health involvement is helpful in furthering the patient understanding of the treatment goals and in continuing the education of how to use the injectable medication and why this is being prescribed. The DXA is repeated at the first follow-up visit and an increase of 2 to 5 percent is expected when compared to the initial DXA scan. If this is not present, the patient is sent for a full secondary osteoporosis workup involving the laboratory tests mentioned previously in this chapter. The DXA is repeated at year 2 and the results of the anabolic therapy are discussed with the patient. The discussion at this time also involves placing the patient on an antiresorptive medication such as alendronate or denosumab and the patient is then sent back to their primary care physician for continuation of care. This follow-up has been shown to be a contributor to significantly better results in terms of improving patients’ pain and increasing their function when treating patients with VCFs. The combination of treating the fracture and the underlying disorder was shown to produce statistically significantly better results than simply treating the VCF alone.⁵

Table 34.2 Follow-up after vertebral augmentation

1.	Follow-up visit—2 weeks (CPT 99213)
2.	Nurse Injection Training of Patient (CPT 96372)
3.	DXA scan (CPT Code 77080 and 76077 if VFA is performed)
4.	Home Health Dispatched with physical therapy focus on lumbar extension training and core muscle strengthening. Injection training is reviewed (Code G0180)
5.	Follow-up visit—1 year (CPT 99213)
6.	DXA scan (CPT Code 77080 and 76077 if VFA is performed)
7.	Follow-up visit—2 year (CPT 99213)
8.	DXA scan (CPT Code 77080 and 76077 if VFA is performed)
9.	Follow-up of osteoporosis treatment with injection of maintenance medication (CPT 96372) or with initiation of noninjectable antiresorptive medication