Osteoporosis is a skeletal disorder characterized by a progressive loss of bone mass and a decline in bone density and quality that results in increased bone fragility and a higher fracture risk. Poor bone mass acquisition during adolescence and bone loss during the sixth decade of life are the main processes responsible for osteoporosis. The various types are as follows:

• Most commonly asymptomatic.
• Insidious and progressive development of dorsal kyphosis (dowager’s hump), loss of height, and skeletal pain typically associated with fracture; reduced gait speed or grip strength; other physical findings related to other conditions with associated increased risk for osteoporosis such as nodular thyroid, hepatic enlargement, jaundice, cushingoid features (see “Risk Factors” and Boxes 1 and 2).

Normal bone turnover involves balance between process of bone resorption and bone formation. Osteoclasts resorb bone, and osteoblasts secrete bone matrix for building bone. In postmenopausal women, rate of bone turnover increases after loss of ovarian function, leading to progressive bone loss.

Several fracture risk calculation tools have been developed. Clinical risk factors used in the World Health Organization Fracture Risk Assessment Tool (WHO FRAX) 10-yr fracture risk calculator are summarized in Box 3.

• Malignancy (multiple myeloma, lymphoma, leukemia, metastatic carcinoma)
• Primary hyperparathyroidism
• Osteomalacia
• Paget disease
• Osteogenesis imperfecta: Types I, III, and IV

• History and physical examination with appropriate evaluation for risk factors and secondary causes. Medications associated with osteoporosis are summarized in Table 1. Investigations for secondary osteoporosis are summarized in Box 4.
• WHO guidelines for the diagnosis of osteoporosis are based on bone mineral density (BMD) measurements of the hip or spine in g/cm² and are reported as a T score.
• Dual-energy x-ray absorptiometry (DEXA) is the gold standard for screening and monitoring changes in BMD due to excellent precision, widespread availability, low cost, and minimal radiation exposure.
• DEXA (Fig. 1) is indicated in all women 65 yr and older and in postmenopausal women younger than 65 yr of age who are at risk for fracture (e.g., weight <127 lbs, parental history of hip fracture, use of medications that cause bone loss, current smoking, excessive alcohol use, rheumatoid arthritis, or presence of diseases that cause bone loss). Clinical indications for bone densitometry are summarized in Table 2. Causes of erroneous bone mineral density measures by DEXA in the lumbar spine are summarized in Table 3.
• FRAX questionnaire (Fig. 2): Use of FRAX calculator (www.sheffield.ac.uk/FRAX/) is proposed by the U.S. Preventive Services Task Force (USPSTF) to determine the need for screening in women between the ages of 50 and 64. If the FRAX 10-yr major osteoporotic risk is greater than or equal to 9.3%, the USPSTF recommends screening with DEXA scan.
• Currently, routine testing in men for osteoporosis is not recommended unless there are clinical manifestations of low bone mass.
• Recommendations as to when to repeat bone density testing should be based on initial T scores (Fig. 3). Data from the Study of Osteoporotic Fractures indicates that in women with normal bone density or mild osteopenia, repeat testing might not be necessary for another 10 to 15 yr. For women with moderate osteopenia, a screening interval of 3 to 5 yr may be appropriate. For women with advanced bone loss/osteoporosis, testing every 1 to 2 yr is recommended.

Figure 3 Diagnosis and management of osteoporosis.

• CMP
• CBC
• TSH
• 24-hr urinary calcium levels and 26-hydroxyvitamin D level may be helpful in evaluating for secondary causes of osteoporosis
• Consider celiac panel and serum protein electrophoresis
• Biochemical markers of bone remodeling may be useful to predict rate of bone loss and/or follow therapy response. Specific biochemical markers (listed below) are followed to document response to therapy.
  1. High-turnover osteoporosis: High levels of resorption markers (lysyl pyridinoline, deoxy lysyl pyridinoline, n-telopeptide of collagen cross-links, C-telopeptide of collagen cross-links) and formation markers (osteocalcin and bone-specific alkaline phosphatase); indicates accelerated bone loss responding best to antiresorptive therapy
  2. Low or normal-turnover osteoporosis: Normal or low levels of the markers of resorption and formation (see “high-turnover osteoporosis” listed previously); no accelerated bone loss; responds best to drugs that enhance bone formation

• Bone mineral density (BMD) determination (see “Workup”) should be performed on all women with determined risk factors and/or associated secondary causes. Criteria for the diagnosis of osteoporosis based on measurement of bone density and T score are summarized in Table 4.
  1. Normal: BMD <1 SD below the young adult reference mean
  2. Osteopenia: BMD 1 to 2.5 SD below the young adult reference mean
  3. Osteoporosis: BMD >2.5 SD below the young adult reference mean
• For patients undergoing treatment: The frequency of BMD monitoring is controversial and many experts recommend that clinicians should not monitor BMD during the initial 5-yr drug treatment period because no studies have proven that such monitoring improves fracture outcomes.
  1. X-ray exam of appropriate part of skeleton (Figs. 4 and 5) is indicated to evaluate clinical osteoporotic fracture only.

Prevention:

• Identification and minimization of risk factors
• Appropriate diagnosis and treatment of secondary causes
• Behavioral modification: Proper nutrition, physical activity (specifically weight-bearing activity), fracture prevention strategies, fall risk reduction

• Vitamin D supplement: 600 IU/day for persons 19 to 70 yr of age and 800 IU/day for persons 71 yr and older. Recommended supplementation of calcium and vitamin D is summarized in Table 4.
• Calcium supplement: The recommended dietary intake of calcium for women 19 to 50 yr of age and men 19 to 70 yr of age is 1000 mg/day; women older than age 50 and men older than age 70 require 1200 mg/day. Calcium intake above 2500 mg/day (2000 mg/day in persons >50 yr of age) should be avoided. Consumption of calcium-rich foods and beverages is the preferred approach to ensuring adequate calcium intake.¹
• Oral bisphosphonates (alendronate, risedronate): Decrease bone resorption by attenuating osteoclast activity. They are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk. The bisphosphonates differ in binding affinity, dose frequency, and route of administration. To facilitate absorption, most oral bisphosphonates are taken on an empty stomach with a full glass of water. Patients are instructed to remain in a sitting or standing position for 30 to 60 min. Contraindications include esophageal disorders, inability to remain standing for 30 to 60 min after taking the medication, chronic kidney disease, and Roux-en-Y gastric bypass procedures. Adverse side effects include gastroesophageal reflux disease, esophagitis, transient hypocalcemia, musculoskeletal pain, renal impairment, ocular side effects, jaw necrosis, and atypical femur fracture.
• Biologic agents: Denosumab is a human monoclonal antibody that inhibits osteoclast formation and prevents resorption for treatment of postmenopausal osteoporosis. It is used as a second-line pharmacologic treatment to reduce the risk of fractures in post-menopausal females diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of biphosphonates.² Dosage is 60 mg subcutaneously every 6 mo. Romosozumab is a monoclonal antibody that increases bone formation and decreases bone resorption by binding to sclerostin. It may be considered for patients who are at high risk for fracture and cannot tolerate any other osteoporotic therapies. Dosage is two consecutive subcutaneous injections (105 mg each) for a total dose of 210 mg once monthly. It should not be used in patients who have had a myocardial infarction or stroke in the past yr.
• Zoledronic acid: A bisphosphonate given by IV infusion over at least 15 min, 5 mg once per yr may be used in patients who are unable to tolerate oral bisphosphonates. It is contraindicated in patients with acute renal failure.
• Teriparatide is a recombinant human parathyroid hormone used for postmenopausal women with osteoporosis who are at high risk for fracture, especially vertebral fractures. It is also used in men with primary or hypogonadal osteoporosis who are at high risk of fracture. It is administered by injection 20 mcg daily, subcutaneously into the thigh or abdominal wall. Use for more than 2 yr is not recommended. It stimulates bone formation and reduces the risk of fracture but may increase the risk of stroke in older women with osteoporosis. Common side effects include headaches, myalgia, hypercalcemia, and hypercalciuria. Trials involving abaloparatide, a selective activator of the parathyroid hormone type 1 receptor, have also shown reduced risk of new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Use of teriparatide is followed by a biphosphonate upon its discontinuation in females with primary osteoporosis and a very high risk of fractures.²
• Estrogen prescription drugs or raloxifene should not be prescribed to treat women with osteoporosis.

• Lifelong attention to behavior modification (nutrition, physical activity, fracture prevention strategies) and compliance with pharmacologic intervention. Recommendations include weight-bearing and muscle-strengthening exercises, smoking cessation, reduced alcohol intake, and adoption of fall prevention strategies.
• There is little evidence to guide physicians about long-term bisphosphonate therapy. The decision to continue drug therapy beyond 5 yr should reflect reassessment of risk and benefit. The risks of atypical fracture of the femur and osteonecrosis of the jaw (ONJ)² increase after 5 yr of bisphosphonate use². It is reasonable to consider a drug holiday in postmenopausal women who are not at high fracture risk after 3 yr (IV) to 5 yr (oral) of bisphosphonate therapy. Continued treatment may be advisable in those at highest risk.
• Continuing need to eliminate high-risk factors when possible and to optimally manage secondary causes of osteoporosis.

Goals for diagnosis and treatment include identification of women at risk; initiation of lifelong preventive measures for all women; institution of treatment modalities that will result in a decrease in fracture risk; and reduction of morbidity, mortality, and unnecessary institutionalization, thereby improving quality of independent life and productivity. Table 5 summarizes the effect of major treatment options on the risk of vertebral, nonvertebral, and hip fractures.