Management of osteoporosis

Key Points

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It is estimated that more than 9% of adults older than the age of 50 years have osteoporosis at either the femoral neck or lumbar spine.
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In Canada, the lifetime risk for hip fracture is estimated to be 8.9% for women and 6.7% for men.
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Strategies to evaluate and treat men and women at risk are critical to reduce fracture burden.
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Effective evaluation and treatment include a workup for secondary causes of low bone mass; lifestyle modification; fall prevention; calcium and vitamin D supplementation; and when appropriate, therapy with an antiresorptive or anabolic agent.
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Antiresorptive agents include the bisphosphonates, which are available in oral and intravenous forms; denosumab, a monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL); and raloxifene, an estrogen agonist-antagonist.
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Anabolic agents approved in the United States include teriparatide (recombinant human parathyroid hormone [rhPTH] 1-34); both rhPTH 1-34 and rhPTH 1-84 are available in Europe, abaloparatide (PTHrp 1-34), and romosozumab, a humanized monoclonal antibody against sclerostin.
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The appropriate duration of antiresorptive therapy and the use of drug holidays are important issues that should be decided on thorough shared decision making by weighing the benefits of fracture prevention and potential long-term side effects.

Introduction

A comprehensive management plan for osteoporosis should include evaluation of possible secondary causes for osteoporosis, assessment of fracture risk, interventions that reduce the risk for future fractures, and treatment of patients with acute fractures. Assessment of fracture risk is critical for making cost-effective treatment decisions in individual patients. It is estimated that more than 9% of adults older than the age of 50 years have osteoporosis at either the femoral neck or lumbar spine. Worldwide, one in three women older than age 50 years and one in five men will experience an osteoporotic fracture. In Canada, the lifetime risk for hip fracture is estimated to be 8.9% for women and 6.7% for men.

Low bone mass increases fracture risk; age, gender, and smoking among others are independent risk factors for fracture and are important for assessing fracture risk in the Fracture Risk Assessment (FRAX) tool ( https://www.sheffield.ac.uk/FRAX/ ). This chapter focuses on the management of osteoporosis and covers guidelines for treatment; pretreatment evaluation, including exclusion of secondary causes of low bone mass; nonpharmacologic therapies, including exercise; fall prevention; calcium and vitamin D supplementation; drug therapies; and treatment of fractures. Identification of patients at risk for fracture based on bone mineral density (BMD) and clinical risk factors is discussed in Chapter 199 .

Recommendations for Treatment

In 2008, the University of Sheffield in coordination with the World Health Organization (WHO) published FRAX, a fracture risk assessment tool ( http://www.shef.ac.uk/FRAX ), and the National Osteoporosis Foundation (NOF) released new guidelines for the prevention and treatment of osteoporosis in the United States. Previous guidelines from the NOF and the American Association of Clinical Endocrinologists were based on previous fracture, BMD T-score, and risk factors but did not incorporate many of the risk factors used in the FRAX model and often resulted in treatment recommendations for lower risk patients. NOF guidelines (Clinician Guide to Prevention and Treatment of Osteoporosis) are available at https://my.nof.org/bone-source/education/clinicians-guide-to-the-prevention-and-treatment-of-osteoporosis ).

Indications for treatment for osteoporosis are summarized in Box 202.1 . The FRAX tool allows for assessment of 10-year fracture risk in over 65 country-specific databases and calculates fracture risk on the basis of gender, height, previous fragility fracture as an adult, parental history of hip fracture, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, and alcohol use. The United States is the only county with ethnicity (Caucasian, Black, Hispanic, Asian) in the model. The NOF guidelines and FRAX are applicable to previously untreated postmenopausal women over age 40 and men older than 50 years ( Fig. 202.1 ).

Box 202.1

Indications for Therapy In Postmenopausal Women And Men Older Than 50 Years Of Age

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After hip or spine fracture
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BMD T-score in spine or proximal femur ≤−2.5
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BMD between −1 and −2.5 and one of following:
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  10-year risk of major fracture of ≥20% ^a
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  10-year risk of hip fracture of ≥3% ^a

The FRAX model has limitations and should be used as a tool to make treatment decisions in combination with clinical judgment. FRAX risk factors are categorical (yes/no), risk factors are more complex, and “doses” of these risk factors are not accounted for in the model. Examples include prior fracture (single vs multiple), glucocorticoids (low vs high dose), current smoking (number of packs per day, past smoking), rheumatoid arthritis (mild vs severe), and alcohol (3 units per day vs more) use. The model is hip-centric, with no ability to use lumbar spine bone mineral density (BMD), and thus underestimates fracture risk when spine bone mineral density is lower than that at the hip. FRAX does not adjust risk in patients with rapid bone loss; these patients are often treated for prevention of bone loss even when fracture risk is below treatment thresholds. It is only used in treatment naïve patients, not those on treatment. It does not include risk factors such as fall risk or bone turnover rate. The Garvin Institute has an online fracture risk calculator that includes the number of fractures and falls and calculates fracture risk for 5 and 10 years ( https://www.garvan.org.au/promotions/bone-fracture-risk/calculator ). Nonetheless, FRAX and the 2008 NOF treatment guidelines for osteoporosis offer a significant advantage by providing health care personnel with treatment recommendations on the basis of BMD (or body mass index if BMD has not been measured) and clinical risk factors and by predicting absolute, not relative fracture risk.

Evaluation for Secondary Osteoporosis

Management of a patient with osteoporosis requires attention to possible secondary causes of low BMD. Many individuals with low bone mass have specific underlying diseases or take medications that affect bone metabolism ( Box 202.2 ). Switching medications to alternatives that do not adversely affect bone mass or providing preventive therapy should be considered. Laboratory investigation in patients with low bone mass is recommended because up to 50% have underlying disorders such as vitamin D deficiency or hypercalciuria. Routine laboratory tests to identify the common causes of secondary osteoporosis include a complete blood count, erythrocyte sedimentation rate, serum chemistry profile, 25-hydroxyvitamin vitamin D, thyroid-stimulating hormone, parathyroid hormone (PTH), and 24-hour urine for measurement of calcium excretion ( Box 202.3 ). Correction of the underlying cause may have a substantial impact on BMD and fracture risk, in some cases may be the only intervention required, and should be done before starting any pharmacologic therapy.

Box 202.2

Conditions, Diseases, And Medications That Cause Or Contribute To Osteoporosis And Fractures

From Cosman F, de Beur SJ, LeBoff MJ, et al: Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359–81 .

Lifestyle factors
Alcohol abuse	Excessive thinness	Excess vitamin A
Frequent falling	High salt intake	Immobilization
Inadequate physical activity	Low calcium intake	Smoking (active or passive)
Vitamin D insufficiency
Genetic diseases
Cystic fibrosis	Ehlers-Danlos	Gaucher’s disease
Glycogen storage diseases	Hemochromatosis	Homocystinuria
Hypophosphatasia	Marfan syndrome	Menkes steely hair syndrome
Osteogenesis imperfecta	Parental history of hip fracture	Porphyria
Riley-Day syndrome
Hypogonadal states
Androgen insensitivity	Anorexia nervosa	Athletic amenorrhea
Hyperprolactinemia	Panhypopituitarism	Premature menopause (<40 years)
Turner’s and Klinefelter’s syndromes
Endocrine disorders
Central obesity	Cushing’s syndrome	Diabetes mellitus (types 1 and 2)
Hyperparathyroidism	Thyrotoxicosis
Gastrointestinal disorders
Celiac disease	Gastric bypass	Gastrointestinal surgery
Inflammatory bowel disease	Malabsorption	Pancreatic disease
Primary biliary cirrhosis
Hematologic disorders
Hemophilia	Leukemia and lymphomas	Monoclonal gammopathies
Multiple myeloma	Sickle cell disease	Systemic mastocytosis
Thalassemia
Rheumatologic and autoimmune diseases
Ankylosing spondylitis	Other rheumatic and autoimmune diseases
Rheumatoid arthritis	Systemic lupus
Neurological and musculoskeletal risk factors
Epilepsy	Multiple sclerosis	Muscular dystrophy
Parkinson’s disease	Spinal cord injury	Stroke
Miscellaneous conditions and diseases
AIDS/HIV	Amyloidosis	Chronic metabolic acidosis
Chronic obstructive lung disease	Congestive heart failure	Depression
End-stage renal disease	Hypercalciuria	Idiopathic scoliosis
Posttransplant bone disease	Sarcoidosis	Weight loss
Medications
Aluminum (in antacids)	Anticoagulants (heparin)	Anticonvulsants
Aromatase inhibitors	Barbiturates	Cancer chemotherapeutic drugs
Depo-medroxyprogesterone (premenopausal contraception)	Glucocorticoids (≥5 mg/day prednisone or equivalent for ≥3 months)	GnRH (gonadotropin-releasing hormone) agonists
Lithium cyclosporine A and tacrolimus	Methotrexate	Parental nutrition
Proton pump inhibitors	Selective serotonin reuptake inhibitors
Tamoxifen® (premenopausal use)	Thiazolidinediones (such as Actos® and Avandia®)	Thyroid hormones (in excess)

Box 202.3

Exclusion Of Secondary Causes Of Osteoporosis

Consider the following diagnostic studies for secondary causes of osteoporosis

Blood or serum
- Complete blood count (CBC)
- Chemistry levels (calcium, renal function, phosphorus, and magnesium)
- Liver function tests
- Thyroid-stimulating hormone (TSH) +/− free T4
- 25(OH)D
- Parathyroid hormone (PTH)
- Total testosterone and gonadotropin in younger men
- Bone turnover markers

Consider in selected patients

Serum protein electrophoresis (SPEP), serum immunofixation, serum-free light chains
Tissue transglutaminase antibodies (immunoglobulins A and G)
Iron and ferritin levels
Homocysteine
Prolactin
Tryptase
Urine
- 24-h urinary calcium

Consider in selected patients

Protein electrophoresis (UPEP)
Urinary free cortisol level
Urinary histamine

Treatment

Nonpharmacologic Approaches

Treatment can be directed at both improving bone mass and quality and at prevention of falls, the initiating event for many osteoporotic fractures. There are a number of nonpharmacologic approaches that are helpful to achieving one or both of these aims, and these are summarized next. When available, this section focuses on evidence-based approaches or, in the absence of evidence, general consensus.

Physical therapy and balance training

Assessment of propensity for falls and modification of such risk factors through effective intervention when possible should be undertaken. A multidisciplinary team approach for prevention of falls including physical therapy and balance training has been shown to be efficacious. The Timed Up and Go test was shown to discriminate between future recurrent fallers and nonfallers in the 12-months after a hip fracture in frail older adults.

The Pediatric Osteoporosis Prevention study (POP) showed that a physical activity (PA) program in children from Tanner stage 1 to 5 resulted in gains in BMD, bone size, and muscle strength, and children with daily PA demonstrated a reduction in fracture incidence in both sexes when compared to PA 1 to 2 days per week. PA-induced BMD benefits attained in childhood have BMD benefits in adulthood with demonstrated lower fracture incidence. Weight-bearing exercise results in skeletal mechanotransduction, resulting in signals to osteocytes that increase bone strength with small gains in bone mass. Exercise in children when combined with calcium intake appears to be most effective before attainment of peak bone mass, which occurs at age 25–30 years. Exercise alone does not prevent postmenopausal bone loss when estrogen deficiency upregulates bone resorption. Combining exercise programs with calcium supplementation or other therapeutic interventions may be more effective in maintaining bone mass than either intervention alone.

Although previous studies in younger women showed improved BMD, a randomized trial using 10 minutes of whole body vibration daily for male and female patients older than age 60 years (n = 174) in independent living conditions did not demonstrate any significant effects on volumetric BMD or bone biomarkers (propeptide of type I collagen, carboxy-terminal telopeptide). A systemic review and metaanalysis of 10 trials with 462 postmenopausal women showed improvement of lumbar spine and femoral neck BMD in women younger than age 65.

Calcium and Vitamin D Supplementation

Recent studies have resulted in conflicting recommendations about the optimal intake of calcium and vitamin D. The Institute of Medicine (IOM) emphasized the limitations of the existing studies on the benefits and risks of calcium and vitamin D supplementation. Controversy has surrounded the IOM conclusion that a serum 25-hydroxyvitamin D (25OHD) level of 20 ng/mL was adequate vs the accepted definition of vitamin D sufficiency of more than 30 ng/mL.

A 2011 metaanalysis conducted for the U.S. Preventive Services Task Force (USPSTF) concluded that combined vitamin D (300 to 1100 IU/d) and calcium supplementation (500 to 1200 mg/d), but not vitamin D supplementation alone, can reduce fracture risk on older adults. These effects are smaller in community-dwelling elderly or postmenopausal women than in institutionalized elderly.

Recommendations for supplementation of calcium and vitamin D are presented in Table 202.1 ; however, in some instances, larger doses of vitamin D may be necessary. The 2021 IOM recommendations for calcium and vitamin D have different guidelines for recommended daily amounts.

Table 202.1

Recommended Supplementation of Calcium and Vitamin D

Individual Age Categories	Elemental Calcium	Vitamin D ^a
Birth–6 mo	400 mg	200 IU
6–12 mo	600 mg	200 IU
1–10 yr	800 mg	200 IU
11–24 yr	1200–1500 mg/day	400 IU
Women and men 25–65 yr: premenopausal or postmenopausal women taking estrogen	1000 mg/day	400–600 IU
Postmenopausal women, no estrogen	1500 mg/day	400–600 IU for men and women >65 yr
Pregnant and lactating women	1200–1500 mg/day	400 IU
National Osteoporosis Foundation guidelines	1200 mg	800–1000 IU

a These recommendations are guidelines and may be sufficient for healthy individuals with normal 25-hydroxyvitamin D levels. In many circumstances, however, they are insufficient .

Assessment of vitamin D status by measuring serum 25OHD levels is required before initiating some pharmacologic therapy. Since hypocalcemia may occur in patients with low vitamin D levels treated with potent antiresorptive agents such as denosumab and zoledronate, correction of vitamin D deficiency is required. Severe vitamin D deficiency can result in osteomalacia, a failure of bone mineralization (see Chapter 204 ). Osteomalacia may be associated with muscle weakness indicating the importance of vitamin D in muscle function. Initial treatment should be with vitamin D, not antiresorptive agents. Striking gains in BMD with vitamin D replacement are a result of rapid mineralization of osteoid.

Although some individual studies have shown primary fracture risk reduction with cholecalciferol, metaanalyses have shown no effect of vitamin D treatment when used alone on fracture risk while calcium plus vitamin D has been shown to reduce the risk of both nonvertebral and hip fractures. Chapuy and colleagues demonstrated in two large randomized, placebo-controlled trials that institutionalized older adults with osteoporosis randomized to a combination of calcium and vitamin D supplementation significantly reduced their risk for vertebral, nonvertebral, and hip fractures.

A metaanalysis of the effect of oral vitamin D on prevention of nonvertebral fractures concluded that its efficacy for fractures is dose dependent, with higher doses reducing fractures by at least 20%. A systematic review concluded that treatment of vitamin D deficiency in asymptomatic persons might reduce mortality risk in institutionalized older adults and the risk for falls but not for fractures.

There have been conflicting reports of increased risk for cardiovascular events with calcium supplementation since Bolland’s metaanalysis of 11 trials showed a 30% increase in the risk for myocardial infarctions. Subsequent studies have found no association, including two randomized trials that were larger and had longer follow-up periods than the Bolland study. Recent evidence from two systemic reviews and metaanalyses have been published with conflicting results. A systematic review by Chung et al. found that calcium intake within tolerable upper intake levels (2000–2500 mg/day) was not associated with cardiovascular disease risk in generally healthy adults. Yang et al. found no increased risk of adverse cardiovascular outcomes for dietary calcium intakes ranging from 200 to 1500 mg/d, while calcium supplements increased the risk of adverse cardiovascular outcomes from 8% to 21%.

Other Lifestyle Modifications

Smoking is directly toxic to bone cells, and population studies have shown that smokers have lower BMD and a greater annual rate of bone loss than nonsmokers. Current smokers have an increased risk for hip fracture. Although limited data are available on the benefits of smoking cessation, discontinuation of tobacco use has resulted in favorable effects on bone metabolism in some small trials. The Nurses’ Health Study found that fracture risk fell but only after 10 or more years of abstinence from smoking.

Alcohol in moderation may have a positive effect on BMD. Three or more drink equivalents per day should be discouraged given its association with an increased propensity for falls and risk for fracture. A metaanalysis demonstrated a J-shaped relationship between alcohol consumption and risk for hip fracture, with persons consuming less than one or more than two drinks per day having a higher risk for hip fracture.

Excessive caffeine use has been associated with lower dietary calcium intake, decreased intestinal calcium absorption, and hypercalciuria, and it has been linked to an increased risk for fracture. Moderation of intake is required in those at risk. Caffeine intake in the range consumed by most women is not an important risk factor for osteoporosis.

Prevention of Falls

Almost one third of persons older than 70 years will sustain a fall each year, with higher numbers being reported in women, older individuals, and nursing home residents. Falls are a major source of morbidity and increased mortality, and about 5% result in a fracture. In the Dubbo Osteoporosis Epidemiology Study, falling in the previous year was the factor that most highly correlated with risk for incident hip fracture in more than 1600 nonosteoporotic men and women observed for 15 years (hazard ratio [HR], 1.9 and 2.1, respectively).

Most falls are predictable, with readily identifiable risk factors. Box 202.4 outlines risk factors for falls dividing them into environmental, medical, neurologic, and musculoskeletal risk factors. Studies have shown that risk for falls is related to a history of falls; use of medications or conditions that predispose to falls, including cognitive, visual, or auditory impairment; decreased muscle strength; increased body sway; and poor balance. Such conditions are more prevalent in older individuals, and the propensity to fall increases as the number of risk factors rises.

Box 202.4

Risk Factors for Falls

From National Osteoporosis Foundation. Health professional’s guide to rehabilitation of the patient with osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003 .

Environmental risk factors

Lack of assistive devices in bathrooms
Obstacles in the walking path
Loose throw rugs
Slippery conditions
Low-level lighting

Medical risk factors

Age
Medications causing sedation (narcotic analgesics, anticonvulsants, psychotropics)
Anxiety and agitation
Orthostatic hypotension
Arrhythmias
Poor vision
Dehydration
Previous falls or fear of falling
Depression
Reduced problem solving or mental acuity and diminished cognitive skills
Vitamin D insufficiency [serum 25-hydroxyvitamin D (25(OH)D) < 30 ng/mL (75 nmol/L)]
Urgent urinary incontinence
Malnutrition

Neurological and musculoskeletal risk factors

Kyphosis
Reduced proprioception
Poor balance
Weak muscles/sarcopenia
Impaired transfer and mobility
Deconditioning
Diseases listed in Box 202.2

Thorough evaluation of the risk for falls and careful clinical assessment of medications and conditions that may contribute to such risk or bone loss can readily be performed in the office by a trained health care provider. Assessing all factors that influence the propensity for falls may be better accomplished with more comprehensive methods, and a multidisciplinary team approach can be effective.

Controlled studies evaluating tai chi have shown that this type of exercise reduces falls and fear of falling and improves muscle strength and activity in older adults.

Hip Pads and Other Assistive Devices

Hip protectors have been shown to prevent hip fractures in compliant participants at increased risk for falling. A study involving 18 nursing homes randomized patients to hard or soft hip protectors and showed a 60% reduction in hip fractures in patients using protectors.

However, not all devices are the same, and not all studies show an effect. Although adherence is poor and the effectiveness remains unclear, high-risk individuals who wear hip pads may reduce their risk for proximal femoral fracture. Given the benign nature of this intervention, it is worth considering in older adults with osteoporosis who are at increased risk for falls.

Pharmacologic Interventions

Hormone Replacement Therapy

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