Osteoporosis is a skeletal disorder characterized by compromised bone strength, which predisposes to the development of fragility fractures. Bone strength is determined by both bone mass and bone quality. The diagnosis of osteoporosis is established by the presence of a true fragility or, in patients who have never sustained a fragility fracture, by measurement of bone mineral density (BMD).

Fragility fractures are fractures that occur spontaneously or following minimal trauma, defined as falling from a standing height or less. Fractures of the vertebrae, hips, and distal radius (Colles fracture) are the most characteristic fragility fractures, but patients with osteoporosis are prone to all types of fractures. Osteoporosis accounts for approximately 1.5 million fractures in the United States each year.

Vertebral fractures cause loss of height, anterior kyphosis (dowager’s hump), reduced pulmonary function, and an increased mortality rate. Approximately one third of all vertebral fractures are painful, but two thirds are asymptomatic. Hip fractures are associated with permanent disability in nearly 50% of patients and with a 20% higher mortality rate than in the age-matched population without fractures.

 Low BMD (twofold increased risk for every one standard deviation [SD] decrease of BMD)

 Age (twofold increased risk for every decade of age above 60 years)

 Previous fragility fracture (fivefold increased risk for a previous fracture)

 Frequent falls

 Age ≥ 65 years

 Estrogen deficiency plus one risk factor for osteoporosis

 Vertebral deformity, fracture, or radiographic evidence of osteopenia

 Primary hyperparathyroidism

 Glucocorticoid therapy, ≥ 5 mg/day of prednisone for ≥ 3 months

 Monitoring the response to an osteoporosis medication approved by the U.S. Food and Drug Administration (FDA)

Dual-energy x-ray absorptiometry (DXA) is the most accurate and widely used method in current practice. BMD can also be measured by computed tomography (CT) and ultrasound (US). Central densitometry measurements (spine and hip) are the best predictors of fracture risk and have the best precision for longitudinal monitoring. Peripheral densitometry measurements (heel, radius, hands) are more widely available and less expensive.

 T-score: The number of SDs the patient’s value is below or above the mean value for young normal subjects (peak bone mass). The T-score is a good predictor of the fracture risk.

 Z-score: The number of SDs the patient’s value is below or above the mean value for age-matched normal subjects. The Z-score indicates whether or not the BMD is appropriate for age.

 Absolute BMD: The actual BMD expressed in g/cm². This is the value that should be used to calculate changes in BMD during longitudinal follow-up.

Osteoporosis should be diagnosed in any patient who sustains a fragility fracture. In a patient without fractures, the diagnosis can be made on the basis of the BMD T-score at the lowest skeletal site, using the following criteria:

 Calcium

 Creatinine (estimated glomerular filtration rate)

 Alkaline phosphatase

 25-hydroxyvitamin D (25-OHD)

 Testosterone (men)

 Thyroid-stimulating hormone (TSH)

 Celiac disease antibody testing

 Urine (24-hour) calcium, sodium, creatinine

In approximately one third of women and two thirds of men, an abnormality will be detected with this evaluation.

Back pain and tenderness are helpful clues but may be absent because two thirds of vertebral fractures are asymptomatic. Height loss of 2 inches or more and dorsal kyphosis are highly suggestive clinical findings. Lateral spine films and dual-energy x-ray absorptiometry vertebral fracture assessment (VFA) are the most accurate ways to detect existing vertebral fractures.

 Use of sedatives

 Visual impairment

 Cognitive impairment

 Lower extremity disability

 Obstacles to ambulation in the home

 Adequate calcium intake (diet plus supplements): 1000-1200 mg/day for premenopausal women and men; 1200-1500 mg/day for postmenopausal women and men 65 years or older

 Adequate vitamin D intake: 800-1200 U/day (D₃ preferred)

 Regular exercise: aerobic and resistance

 Limitation of alcohol consumption to fewer than 2 drinks/day

 Limitation of caffeine consumption to fewer than 2 servings/day

 Smoking cessation

 Fall prevention

The major bioavailable sources are dairy products and calcium-fortified fruit drinks. The following approximate calcium contents should be assigned for dairy product intake:

Add 300 mg for the general nondairy diet for a reasonable estimate of daily intake.

Low-fat dairy products are the best source of calcium. Calcium supplements should be added when the desired goals cannot be reached with dietary sources. Calcium carbonate and calcium citrate are both well absorbed when taken with meals. Gastric acid is needed for normal calcium absorption; calcium carbonate absorption may be significantly reduced in patients who have achlorhydria or who use a PPI. Calcium citrate absorption is less likely to be affected by PPI use.

There are two natural forms of vitamin D: cholecalciferol (vitamin D₃) and ergocalciferol (vitamin D₂). Fatty fish (D₃) and some fortified milk and cereal products (D₂ and D₃) are good dietary sources. Vitamin D₂ and D₃ supplements are available over the counter in multiple doses, and 50,000-unit vitamin D₂ supplements can be given by prescription. Sunlight exposure raises vitamin D levels but often must be limited for many reasons; therefore, oral vitamin D is the major source for most people. The optimal vitamin D intake is 800 to 1200 units daily.

The serum 25-OHD goal level is 30 to 100 ng/mL. In general, 1000 units (U) daily of vitamin D will raise the serum level by 10 ng/mL. I recommend the following:

Pharmacologic therapy should be advised for anyone who has had a vertebral or hip fracture or who has a T-score less than −2.5. The FRAX tool, developed by the World Health Organization (WHO), is recommended for making treatment decisions in drug-naïve patients with osteopenia (for information, go to www.shef.ac.uk/FRAX). Treatment is advised for those who have a 10-year risk of 3% or higher for hip fracture or 20% or higher for other major osteoporotic fractures.

Bone remodeling is the process that removes old bone and replaces it with new bone (Fig. 8-1). Osteoclasts attach to bone surfaces and secrete acid and enzymes that dissolve away underlying bone. Osteoblasts then migrate into these resorption pits and secrete osteoid, which becomes mineralized with calcium phosphate crystals (hydroxyapatite). Osteocytes serve as the mechanoreceptors that sense skeletal stress and send signals to orchestrate the process of bone remodeling in areas of bone that need renewal.

RANK (receptor activator of nuclear factor κ) is a specific receptor on osteoclasts. RANK-L (RANK ligand) binds to RANK to stimulate osteoclastic bone resorption. Osteoprotegerin is a soluble decoy receptor that binds to RANK-L, preventing it from binding to RANK. Bone resorption is driven by RANK-L and inhibited by osteoprotegerin.

Osteoporosis medications are classified into two main categories: antiresorptive agents and anabolic agents. Antiresorptive medications include the bisphosphonates, denosumab (monoclonal antibody against RANK-L), raloxifene, calcitonin, and estrogens. The only currently available anabolic agent is teriparatide.

Persistently elevated serum parathyroid hormone (PTH) levels (primary hyperparathyroidism) promote osteoclastic bone resorption and bone loss. In contrast, intermittent daily pulses of exogenous PTH actually stimulate osteoblastic bone formation and increase bone mass. Teriparatide is a 34–amino acid fragment of intact PTH that retains the ability to bind to and activate PTH receptors on osteoblasts.

All of the FDA-approved medications listed in the previous table have been demonstrated in randomized controlled trials (RCTs) to significantly reduce vertebral fractures in women with postmenopausal osteoporosis. Hip fractures have also been reduced by alendronate, risedronate, zoledronic acid, and denosumab. Nonvertebral fracture reduction has been reported with alendronate, risedronate, zoledronic acid, denosumab, and teriparatide.

Combinations of antiresorptive agents increase bone mass more than single agents alone, but fracture data are not yet available for such regimens. Furthermore, there are concerns that oversuppression of bone resorption may be harmful. Combinations of anabolic and antiresorptive agents used concurrently have disappointingly shown no greater effects than single agents alone. Studies investigating sequential rather than concurrent use of various agents are currently in progress.

ONJ manifests as persistently exposed bone following an invasive dental procedure. It occurs most often during high-dose IV bisphosphonate therapy for multiple myeloma or bone metastases. ONJ has also been identified in some patients taking bisphosphonates for osteoporosis. Good oral hygiene and regular dental care are the best preventive measures. Temporarily stopping bisphosphonates for invasive dental procedures is a common and reasonable practice but has not been shown to prevent ONJ.

Atypical femoral fractures have been reported in some patients undergoing long-term bisphosphonate therapy (> 5 years). It is not clear whether the fractures resulted from bisphosphonate use or the underlying osteoporosis. Currently, no data exist regarding preventive measures. After 5 years of bisphosphonate use, many providers recommend a 1- to 2-year bisphosphonate “drug holiday” for patients who have osteopenia and a temporary switch to anabolic therapy or other non-bisphosphonate agent for those with previous fractures or very low BMD.

BMD testing to monitor therapy responses is most often repeated after 2 years of treatment. To accurately interpret serial changes, the least significant change (LSC) for the specific instrument must be known. The LSC is a precision estimate that informs the user about the minimum BMD change that should be considered significant. Standard procedures for performing the LSC assessment are available on the International Society for Clinical Densitometry’s Website (www.iscd.org).

Elevation of biomarkers predicts future bone loss. A 30% reduction of biomarkers after therapy is initiated verifies compliance and predicts an increase in bone mass. However, great variability in biomarker measurement limits the utility of this tool.

The common causes of BMD loss on treatment and their management are as follows:

Approximately 1 to 2 million men in the United States have osteoporosis. The diagnostic criteria are the same in men as in women (fragility fracture or T-score ≤ −2.5). Nearly two thirds of osteoporotic men have an identifiable secondary cause of bone loss, most often alcohol abuse, glucocorticoid use, or hypogonadism, including that due to use of a gonadotropin-releasing hormone (GnRH) analog for prostate cancer. Treatment is generally the same as in women although testosterone replacement in hypogonadal men can be an effective adjunctive strategy.

1. Minimize or discontinue sedatives.

2. Correct visual impairment.

3. Prescribe ambulatory aids when appropriate.

4. Make a “fall-proof” home: adequate lighting, carpeting, handrails, non-slip bathroom surfaces, removal of clutter and obstacles to walking.