Osteoporosis

Overview

Definition

Osteoporosis is a metabolic bone disorder characterized by low bone mass and increased bone fragility.

Epidemiology

• Most common metabolic bone disease
• Affects 200,000 million people worldwide
• More common in the elderly (> 50 years of age)
• More common in women than in men, ratio of 4:1
• Most common in postmenoupasal women

Classification

• Primary osteoporosis:
  • Idiopathic:
    • Type 1: postmenopausal
    • Type 2: senile (age-related)
  • Juvenile: usually between 8 and 14 years of age
• Secondary osteoporosis:
  • Can occur at any age
  • Caused by disease, deficiency, or drugs

Etiology

Primary osteoporosis:

• Type I: estrogen deficiency
• Type II: age-related loss of bone mineral density (BMD)
• Risk factors:
  • Age
  • Female gender
  • White or Asian ethnicity
  • Family history
  • Small stature/thin build
  • Amenorrhea
  • Late menarche
  • Early menopause
  • Physical inactivity
  • Alcohol or tobacco use

Secondary osteoporosis:

• Endocrine disorders (hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, hypogonadism, vitamin D deficiency/resistance)
• Bone marrow disorders (multiple myeloma, leukemia, lymphoma)
• GI disorders (gastrectomy, malabsorption syndromes, Crohn’s disease)
• Connective tissue disorders (rheumatoid arthritis, osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome)
• Drug induced (glucocorticoids, anticonvulsants, cyclosporine, heparin, antiretroviral therapy, aromatase inhibitors, proton pump inhibitors, lithium, calcineurin inhibitors)

Pathophysiology

Normal bone physiology

• Bone undergoes continuous remodeling throughout life.
• Bone resorption (by osteoclasts) is followed by bone formation (by osteoblasts).
• Resorption usually takes weeks, while formation can take months.
• During active remodeling, bone is at an increased risk of fracture:
  • New bone is less densely mineralized.
  • Collagen maturation is impaired.
• Remodeling rate doubles by the age of menopause and triples 13 years later.
• Bone mass peaks during the 3rd decade of life and then gradually decreases.

Pathogenesis of osteoporosis

• Multifactorial
• Generally caused by imbalance between bone resorption and bone formation
• If bone resorption dominates compared with bone formation, osteoporosis may result.
• Role of estrogen deficiency:
  • Increases number of osteoclasts
  • Decreases number of osteoblasts
  • Increases cytokines critical to osteoclast recruitment:
    • Interleukin-1 (IL-1)
    • Interleukin-6 (IL-6)
    • Tumor necrosis factor (TNF)-α
    • Receptor activator of nuclear factor-κB ligand (RANKL)
  • Decreases OPG (osteoprotegerin), which is released by preosteoblasts, binds to RANKL, and serves as an endogenous suppressor of osteoclast function

Clinical Presentation

• Clinically silent, until fracture occurs
• Vertebral fracture:
  • Most common
  • Commonly asymptomatic
  • Can lead to loss in height
  • Angular kyphosis (may lead to restrictive lung disease and dyspnea)
  • Diffuse back pain
• Hip fracture: affects up to 15% of women and 5% of men by 80 years of age
• Distal radius fracture (Colles’ fracture)
• Other fractures:
  • Ribs
  • Humerus
  • Pelvis

Diagnosis

History

• Smoking/alcohol
• Poor nutrition
• Physical activity
• Family history
• Presence of certain diseases (e.g., Crohn’s disease, rheumatoid arthritis)
• Medications (e.g., steroids)

Physical exam

• Height and weight measurements
• Short stature + kyphosis

Clinical criteria

• Presence of fragility fracture
• FRAX (fracture risk assessment tool):
  • Computer-based calculator
  • Estimates 10-year risk of hip fracture and major osteoporotic fracture
  • For untreated patients between 40 and 90 years of age based on risk factors

Laboratory studies

• Calcium/phosphorus
• Total protein/albumin
• Alkaline phosphatase
• Creatinine
• 25-hydroxyvitamin D
• CBC

Dual-energy X-ray absorptiometry (DEXA)

• Method of choice for assessing bone mass density in postmenopausal women 
• Criteria applicable to post-menopausal women and men > 50 years of age:
  • T-score:
    • Standard deviation difference between the patient’s BMD and the reference BMD of a young population
    • Normal bone mass density is < 1 standard deviation below the mean.
    • T-score of –1 to –2.5 standard deviation indicates osteopenia.
    • T-score of < –2.5 standard deviation indicates osteoporosis.
  • Z-score: 
    • SD difference between patient’s BMD and that of age-matched population
    • < –2.0 indicates osteoporosis.
• Indications for screening:
  • Postmenopausal women should begin screening by 65 years of age.
  • Postmenopausal women with risk factors should begin screening at 50 years of age:
    • Tobacco smoking
    • Rheumatoid arthritis
    • Hip fracture in a parent
    • BMI < 21 kg/m²
    • Fracture after menopause

Management

Prevention/lifestyle modifications

• Regular weight-bearing exercise
• Adequate calcium and vitamin D intake
• Smoking cessation
• Avoidance of heavy alcohol consumption
• Fall prevention

Indications for pharmacologic treatment in postmenopausal women

• History of fragility fracture
• DEXA T-score < –1
• Elevated 10-year fracture risk using the FRAX online risk calculator

Indications for treatment in men and younger patients

• Less well defined
• Fragility fractures
• FRAX estimations and BMD measurements can be used.

Medications

• Calcium and vitamin D levels should be normalized prior to starting. medications
• Bisphosphonates: 1st choice (alendronate, risedronate)
• Hormonal replacement: 
  • Estrogen + progesterone in postmenopausal women:
    • Not routinely indicated because of associated risks
    • Can be used in women with perimenopausal symptoms
  • Testosterone replacement in hypogonadal men
• Other therapies:
  • Anabolic agents (teriparatide, romosozumab)
  • Selective estrogen receptor modulators
  • Denosumab (monoclonal antibody against receptor activator of RANKL)
  • Calcitonin

Prognosis

• Good with appropriate treatments that prevent BMD loss
• Osteoporotic fractures decrease quality of life, longevity, and independence in the elderly population.
• 50% of previously independent patients sustaining a hip fracture become at least partially dependent.
• One osteoporotic fracture increases the risk of subsequent fractures.

Differential Diagnosis

• Osteomalacia: the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization. Usually presents with bone pain and fractures. Treated with calcium and vitamin D supplementation.
• Hyperparathyroidism: conditions of pathologically elevated parathyroid hormone levels. Depending on the pathogenesis, distinctions can be made between 3 forms: primary, secondary, and tertiary hyperparathyroidism. In advanced cases, hyperparathyroidism can present with osteitis fibrosa cystica characterized by pathologic bone fractures. Diagnosis is based on elevated PTH levels, and management depends on the underlying cause.
• Malignant bone tumors: cancerous tumors involving bones or bone marrow. Can present with pain and pathologic bone fractures. Diagnosis is established with imaging and biopsies. Management can involve surgical resection, radiation, and chemotherapy.
• Paget’s disease of bone: a disorder of bone metabolism. Most common in patients over 55 years of age. This disorder is usually asymptomatic but can include manifestations such as arthritis, bone pain, and fractures. Diagnosis is established with imaging. Treatment includes bisphosphonates and calcitonin.
• Osteogenesis imperfecta: a genetic connective tissue disorder characterized by bone fragility. Manifests in infancy and early childhood. Multiple fractures can occur and, in some cases, these fractures can occur before birth. There are different types of this disease that vary in severity and prognosis. Diagnosis is established clinically and confirmed with genetic testing. Management involves bisphosphonates and supportive measures.
• Physical abuse: should be ruled out in any patient presenting with multiple fractures, especially vulnerable populations such as the elderly, young children, and patients with mental illness or delay.