Osteoporosis¶

Chapter 423 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 423

Key Clinical Points¶

Osteoporosis is defined as a reduction in bone strength leading to skeletal fragility and fractures.
WHO diagnostic threshold for osteoporosis is a T-score le -2.5 (based on young healthy adults).
Fragility fractures are defined as those occurring from a fall of standing height or less, excluding finger, toes, face, and skull fractures.
Approximately 20% of women will experience a second fracture within 2 years of the first.
Hip fractures carry high morbidity and mortality (20–25% mortality in the year following injury).
Optimal serum 25(OH)D for skeletal health is >75 nmol/L (30 ng/mL).
The RANKL/OPG pathway is the primary mechanism of osteoclast regulation; RANKL promotes formation, while OPG acts as a decoy to inhibit it.
Glucocorticoids are the most common cause of medication-induced osteoporosis.
Silent vertebral fractures occur in approx 1 million cases annually, often identified only via imaging or height loss ge 4 cm.
The FRAX tool integrates non-modifiable and modifiable risks to predict 10-year fracture probability.

DEFINITION & OVERVIEW¶

• Definition: → Osteoporosis is defined as a reduction in the strength of bone that leads to skeletal fragility and fractures. • WHO Criteria: → T-score le -2.5 (defined as 2.5 standard deviations or more below the mean for young healthy adults of the same sex and race). → Note: Many patients with osteopenia (T-score between -1.0 and -2.5) also experience fractures due to larger population size. • Fragility Fractures: → Defined as fractures in adults occurring following a fall from standing height or less. → Exclusions: Finger, toes, face, and skull fractures. → Clinical Note: Recent studies indicate that any traumatic fractures should be regarded as indicative of underlying skeletal fragility and require further evaluation.

EPIDEMIOLOGY¶

• Prevalence: → approx 10.8 million women and 2.5 million men in the US have osteoporosis (T-score < -2.5). → Approximately 40 million Americans have osteopenia (T-score -1.0 to -2.5) and are at risk. • Fracture Statistics: → Hip fractures: Increasing globally; failure to identify the first fragility fracture and intervene is estimated to cost $6 billion to Medicare alone for secondary fractures. → Vertebral fractures: approx 500,000 symptomatic cases/year; however, >1,000,000 occur annually (only one-third are recognized clinically). • Morbidity & Mortality: → Hip fractures: 20–25% mortality in the year following injury. → Long-term impact: approx 30% of survivors require long-term care; many never regain independence. → Silent Fractures: Most vertebral fractures are asymptomatic but serve as a major sign of skeletal fragility and increase risk for subsequent fracture. • Risk Factors (Table 1): → Non-modifiable: Personal history of fracture, family history (1st degree), female gender, advanced age, white race, dementia. → Modentially/Potentially Modifiable: Current cigarette smoking, estrogen deficiency, early menopause (<45 years) or bilateral ovariectomy, prolonged premenstrual amenorrhea (>1 year), poor nutrition (low calcium and vitamin D), alcoholism, impaired eyesight, recurrent falls, inadequate physical activity, poor health/frailty.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Bone Remodeling: → Primary functions: (1) Repair bone microdamage to maintain skeletal strength; (2) Supply calcium from the skeleton when required to maintain serum calcium. → Mechanism: Osteoclasts (monocyte/macrophage lineage) initiate resorption; osteoblasts (mesenchymal lineage) synthesize new organic bone. → Regulation: Influenced by hormones (Estrogen, Androgens, Vitamin D, PTH) and local factors (IGF-I, TGF-β, ILs, prostaglandins). • RANKL/OPG Pathway: → RANKL: Secreted by osteocytes, osteoblasts, and certain immune cells; binds to RANK on osteoclasts to promote differentiation, activation, and survival. → OPG: A humoral decoy secreted by osteoblasts that binds and neutralizes RANKL, leading to a block in osteoclastogenesis. → Wnt Pathway: Activation of Wnt (via mechanical loading or hormones) stimulates bone formation; Sclerostin inhibits Wnt activation. • Calcium Nutrition: → <400 mg/day: Detrimental to the skeleton. → 1000-1200 mg/day: Recommended daily intake for adults. • Vitamin D: → Deficiency leads to rickets (children) or osteomalacia (adults). → Target: >75 nmol/L (30 ng/mL) for skeletal health. • Estrogen Status: → Estrogen deficiency → increased RANKL production and reduced osteoprotegerin (OPG) production, increasing osteoclast formation. → Impact on Bone Type: Trabecular bone is affected preferentially due to larger surface area. • Other Factors: → Physical Activity: High levels during growth increase peak bone mass; in adults, resistance training provides modest gains. → Chronic Diseases (Table 2): Include hypogonadal states (Turner, Klinefelter), endocrine disorders (Cushing, Hyperparathyroidism, Thyrotoxicosis, Diabetes), and rheumatologic disorders (RA, Ankylosing spondylitis). → Medications (Table 3): Glucocorticoids (most common), Cyclosporine, Anticonvulsants, Aromatase inhibitors, Proton pump inhibitors, Thiazolidinediones.

CLINICAL FEATURES¶

• Vertebral Fractures: → Often 'silent' and only identified via imaging or height loss ge 4 cm. → Significant indicator of skeletal fragility regardless of symptoms. • Hip & Other Fractures: → Hip fractures are the most common high-morbidity injuries. → Wrist/Colles' fractures: Incidence increases significantly with age (Figure 2).

DIAGNOSTIC APPROACH¶

Bone Mineral Density (BMD) Testing: → Determine T-score le -2.5 for diagnosis of osteoporosis. → Identify osteopenia if T-score is between -1.0 and -2.5.
FRAX Tool (Figure 7): → Calculate 10-year probability of major osteoporotic fracture or hip fracture. → Inputs: Age, weight, height, smoking status, glucocorticoid use, etc.
Vertebral Imaging (Table 5): → Consider for all women ge 70 and all men ge 80 if BMD T-score at the spine, total hip, or femoral neck is <1.0. → Consider for women 65-69 and men 70-79 if BMD T-score at the spine, total hip, or femoral neck is <1.5. → Consider for postmenopausal women and men ge 50 with specific risk factors: → Low-trauma fracture during adulthood (age ge 50) → Historical height loss of ge 1.5 in. (4 cm) → Prospective height loss of ge 0.8 in. (2 cm) → Recent or ongoing long-term glucocorticoid treatment.

MANAGEMENT & TREATMENT¶

Nutritional Support: → Calcium: Target 1000-1200 mg/day (preferably from dietary sources). → Vitamin D: Supplement to reach >75 nmol/L (30 ng/mL).
Pharmacotherapy: → Bisphosphonates: Effective for preventing hip and nonvertebral fractures (Figure 9). → Denosumab: Reduces crude incidence of vertebral fractures and cumulative risk of hip fractures (Figure 10). → Teriparatide (TPT): Anabolic agent; effective in reducing nonvertebral fragility fractures (Figure 11) and superior to risedronate for vertebral fracture prevention (Figure 13). → Romosozumab: Superior to alendronate for preventing fracture progression when used as a 12-month lead-in before switching to alendronate (Figure 14).
Fracture Liaison Services: → Identify first fragility fracture → initiate intervention → prevent secondary fractures.

COMPLICATIONS & PROGNOSIS¶

• Mortality: → Hip fractures: 20–25% mortality in the first year. • Secondary Fractures: → approx 20% of women will have a second fracture within 2 years of the first.

SPECIAL CONSIDERATIONS¶

• Transgender Population: → Guidelines suggest evaluation of bone density in this population (since 2019). • Medication-Induced: → Glucocorticoids are the primary cause of drug-induced osteoporosis. → Other risks: Cyclosporine, Anticonvulsants, Aromatase inhibitors.

KEY PEARLS & CLINICAL TRAPS¶

• T-score vs. Z-score: T-score is the clinical standard for diagnosis (compared to young adults); Z-score compares patients to peers of same age/sex. → A patient with a 'normal' Z-score may still have a 'pathological' T-score (Figure 6). • Silent Fractures: Most vertebral fractures are asymptomatic; height loss ge 4 cm is a clinical indicator of fracture history. • RANKL/OPG Balance: This is the central molecular switch for bone resorption; RANKL promotes osteoclastogenesis while OPG inhibits it. • Treatment Selection: → Bisphosphonates and Denosumab are standard options. → Teriparatide (anabolic) and Romosozumab are potent alternatives, especially in high-risk patients or those with severe osteoporosis.

Reference Tables¶

TABLE 423-1 Risk Factors for Osteoporosis Fracture NONMODIFIABLE Personal history of fracture as an adult Current…¶

Harrison's 22e, p.3292

NONMODIFIABLE	POTENTIALLY MODIFIABLE
Personal history of fracture as an adult History of fracture in first-degree relative Female gender Advanced age White race Dementia	Current cigarette smoking Estrogen deficiency Early menopause (<45 years) or bilateral ovariectomy Prolonged premenstrual amenorrhea (>1 year) Poor nutrition especially low calcium and vitamin D intake Alcoholism Impaired eyesight despite adequate correction Recurrent falls Inadequate physical activity Poor health/frailty

TABLE 423-2 Diseases Associated with an Increased Risk of Generalized Osteoporosis in Adults Hypogonadal states…¶

Harrison's 22e, p.3296

Hypogonadal states
Turner’s syndrome
Klinefelter’s syndrome
Anorexia nervosa
Hypothalamic amenorrhea
Hyperprolactinemia
Other primary or secondary
hypogonadal states
Endocrine disorders
Cushing’s syndrome
Hyperparathyroidism
Thyrotoxicosis
Diabetes mellitus (both type 1 and 2)
Acromegaly
Adrenal insufficiency
Nutritional and gastrointestinal
disorders
Malnutrition
Parenteral nutrition
Malabsorption syndromes
Gastrectomy
Severe liver disease, especially biliary
cirrhosis
Pernicious anemia
Rheumatologic disorders
Rheumatoid arthritis
Ankylosing spondylitis

Hematologic disorders/malignancy
Multiple myeloma
Lymphoma and leukemia
Malignancy-associated parathyroid
hormone–related peptide (PTHrP)
production
Mastocytosis
Hemophilia
Thalassemia
Selected inherited disorders
Osteogenesis imperfecta
Marfan’s syndrome
Hemochromatosis
Hypophosphatasia
Glycogen storage diseases
Homocystinuria
Ehlers-Danlos syndrome
Porphyria
Menkes’ syndrome
Epidermolysis bullosa
Other disorders
Immobilization
Chronic obstructive pulmonary disease
Pregnancy and lactation
Scoliosis
Multiple sclerosis
Sarcoidosis
Amyloidosis

TABLE 423-3 Drugs Associated with an Increased Risk of Generalized Osteoporosis in Adults Glucocorticoids Cyclosporine…¶

Harrison's 22e, p.3296

Glucocorticoids	Excessive thyroxine
Cyclosporine	Aluminum
Cytotoxic drugs	Gonadotropin-releasing hormone agonists
Anticonvulsants	Heparin
Aromatase inhibitors Selective serotonin reuptake inhibitors	Lithium
	Protein pump inhibitors Thiazolidinediones Androgen deprivation therapies

TABLE 423-4 Indications for Bone Mineral Density Testing • Women aged ≥65 and men aged ≥70; regardless of clinical risk…¶

Harrison's 22e, p.3297

• Women aged ≥65 and men aged ≥70; regardless of clinical risk factors
• Younger postmenopausal women, women in the menopausal transition, and
men aged from 50 to 69 with clinical risk factors for fracture
• Adults who have a fracture at or after age 50
• Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g.,
glucocorticoids at a daily dose >5 mg prednisone or equivalent for >3 months
associated with low bone mass or bone loss

TABLE 423-5 Indications for Vertebral Testing Consider vertebral imaging tests for the following individuals a • All…¶

Harrison's 22e, p.3298

Consider vertebral imaging tests for the following individualsa
• All women aged ≥70 and all men aged ≥80 if bone mineral density (BMD)
T-score at the spine, total hip, or femoral neck is <1.0
• Women aged from 65 to 69 and men aged from 70 to 79 if BMD T-score at the
spine, total hip, or femoral neck is <1.5
• Postmenopausal women and men aged ≥50 with specific risk factors:
• Low-trauma fracture during adulthood (aged ≥50)
• Historical height loss of ≥1.5 in. (4 cm)b
• Prospective height loss of ≥0.8 in. (2 cm)c
• Recent or ongoing long-term glucocorticoid treatment

TABLE 423-6 Biochemical Markers of Bone Metabolism in Clinical Use Bone formation¶

Harrison's 22e, p.3299

Bone formation
Serum bone-specific alkaline phosphatase
Serum osteocalcin
Serum propeptide of type I procollagen
Bone resorption
Urine and serum cross-linked N-telopeptide
Urine and serum cross-linked C-telopeptide

TABLE 423-7 Adequate Calcium Intake¶

Harrison's 22e, p.3301

LIFE STAGE GROUP	ESTIMATED ADEQUATE DAILY CALCIUM INTAKE, mg/d
Young children (1–3 years)	500
Adolescents and young adults (9–18 years)	1300
Men and women (51 years and older)	1200

TABLE 423-8 Elemental Calcium Content of Various Oral Calcium Preparations¶

Harrison's 22e, p.3301

CALCIUM PREPARATION	ELEMENTAL CALCIUM CONTENT
Calcium citrate	60 mg/300 mg
Calcium gluconate	40 mg/500 mg
Calcium carbonate + 5 μg vitamin D 2 (OsCal 250)	250 mg/tablet