Which of the following is most likely the best initial first line therapy for a postmenopausal woman with osteoporosis?

Summary

• Osteopenia & Osteoporosis represent a continuum of conditions that present with a decrease in bone mass and disrupted bone microarchitecture most commonly as a result of increased age, menopause, and metabolic abnormalities.

• Diagnosis is made with a lumbar-based DEXA scan with osteopenia having a T-score of 1 to 2.5 standard deviations below the peak bone mass of a 25-year-old individual, and osteoporosis having a T-score >2.5 standard of deviations below the peak bone mass of a 25-year-old individual.

• Treatment involves a multidisciplinary approach with medical management and physical activity to increase bone mineral density and to help prevent fractures.

Epidemiology

• Incidence

  • 10 million Americans and 200 million people worldwide have osteoporosis

  • 34 million Americans have osteopenia

  • 1.5 million osteoporotic fractures occur each year

    • 700,000 are vertebral fractures

    • 300,000 are hip fractures

    • 200,000 are wrist fractures

• Demographics

  • male: female ratio is 1:4

    • men have a higher prevalence of secondary osteoporosis (60%) including

      • hypogonadism

      • glucocorticoid excess

      • alcoholism

  • age bracket

    • osteoporosis

      • postmenopausal osteoporosis is highest in women aged 50-70 years

      • senile osteoporosis begins after 70 years

      • secondary osteoporosis begins at any age

    • fractures

      • wrist fractures occur most commonly at age 50-60 years

      • vertebral fractures occur most commonly at age 60-70 years

      • hip fractures occur most commonly at age 70-80 years

• Anatomic location

  • vertebral body > peritrochanter femur > distal radius

• Risk factors

  • table of risk factors

Etiology

• Pathophysiology

  • quantitative, not qualitative, disorder of bone mineralization

  • factors

    • failure to build peak bone mass as a young adult

    • bone loss in later life

• Genetics

  • Polymorphisms in the genes for the calcitonin receptor, estrogen receptor-1, type I collagen alpha-1 chain, or the vitamin D receptor have been shown to be associated with osteoporosis

• Associated conditions

  • fragility fractures

    • direct relationship between degree of bone loss and fractures

    • kyphotic deformity can arise from vertebral body fractures

    • pelvic ring insufficiency fractures most often treated with bed rest and analgesia

    • total hip arthroplasty with constrained components are a risk factor for fragility fractures

• Associated with 20% increase in mortality

  • men have higher mortality rates following hip fractures than women

• Associated with increased morbidity

  • reduced quality of life

  • only one-third of patients with hip fractures return to their previous level of function

• History of 1 hip fracture results in up to 10 fold increased risk of 2nd hip fracture

Classification

• Type I vs. Type II Osteoporosis
  	Type I (Post menopausal)	Type II (Senile)
  Age group	Postmenopausal (highest incidence in 50-70 years old)	>70 years old
  Bone affected	Almost exclusively trabecular	Trabecular > cortical
  Bones fractured	Distal radius and vertebral	Hip and pelvis
  Effect on calcium	Net negative change in calcium levels because of decreased intestinal absorption and increased urinary excretion of calcium.	Poor calcium absorption
  Effect on Vit D	Reduced circulating levels of total (but not free) 1,25 dihydroxyvitamin D.

Imaging

• Radiographs

  • indications

    • suspicion of fracture

    • loss of height

    • pain in thoracic or lumbar spine

  • recommended views

    • lateral spine radiograph

    • AP pelvis or hip

  • findings

    • thinned cortices

    • loss of trabecular bone

    • kyphosis

    • codfish vertebra

  • sensitivity and specificity

    • usually not helpful unless > 30% bone loss

• DEXA Scan (Dual Energy Xray Absorptiometry)

  • usually performed in

    • lumbar spine: measures BMD from L2 to L4 and compiles scores

    • hip: measure BMD from femoral neck, trochanter, and intertrochanter region and compiles scores

  • sensitivity and specificity

    • most accurate with the least radiation exposure

• DEXA Scan definitions
  BMD	Absolute, patient-specific score determined from certain anatomic areas
  T-Score	BMD relative to normal young matched controls (30-year-old women)
  Z-Score	BMD relative to similar-aged patients
  Osteopenia	L2-4 lumbar density of 1 to 2.5 standard of deviations (T score -1 to -2.5) below the peak bone mass of a 25-year-old individual
  Osteoporosis	L2-4 lumbar density > 2.5 standard of deviations (T score <-2.5) below the peak bone mass of a 25-year-old individual

Studies

• Labs

  • 25 hydroxyvitamin D level

    • low 25 hydroxy cholecalciferol levels (25 hydroxy vit D) in patients sustaining low energy fractures

  • Other labs may be drawn to rule out other causes of osteoporosis (endocrine, hematologic, malignancy, etc)

    • labs are generally normal in osteoporosis

• Biopsy

  • after tetracycline labeling

  • indications

    • may be helpful to rule out osteomalacia

• Histology

  • thinned trabeculae

  • decreased osteon size

  • enlarged Haversian and marrow spaces

  • osteoclast ruffled border

    • Increases osteoclast ruffled border seen with

      • PTH

      • 1,25 dihydroxy Vit D3

      • Prostaglandin E

    • flattened ruffled border seen with

      • Bisphosphonates

      • Calcitonin

Differential

• Osteoporosis vs. Osteomalacia
  	Osteroporosis	Osteomalacia
  Defintion	Reduced bone mass, normal mineralization	Bone mass variable, reduced mineralization
  Age	Postmenopausal (Type I) or elderly (Type II)	Any age
  Etiology	Endocrine abnormality, age, idiopathic, inactivity, alcohol, calcium deficiency	Vit D deficiency or abnormal vit D pathway, hypophosphatemia, hypophosphatasia, renal tubular acidosis
  Symptoms and signs	Pain and tenderness at fracture site	Generalized bone pain and tenderness
  Xray	Axial fracture predominance	Appendicular fracture predominance, symmetric, includes pseudofractures (Looser zones)
  Serum Ca	Normal	Low or normal
  Serum PO4	Normal	Low or normal
  ALP	Normal	Elevated (except hypophosphatasia)
  Urinary Ca	High or normal	Normal or low (high in hypophosphatasia)
  Bone biopsy	Tetracycline labeling normal	Tetracycline labeling abnormal

Treatment

• Nonoperative

  • lifestyle modification & vitamins

    • indications

      • calcium and Vitamin D

  • pharmacologic treatment

    • indications

      • 2008 National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of Osteoporosis suggests that pharmacologic treatment be considered for

      • postmenopausal women and men >= 50yrs old with:

        • hip/vertebral fracture

        • T score between -1.0 and -2.5 at the femoral neck/spine and

          • 10-year risk of hip fracture ≥ 3% or

          • 10-year risk of major osteoporosis-related fracture ≥ 20% by FRAX calculation

        • T score -2.5 or less at the femoral neck/spine.

    • pharmacologic agents

      • calcium and Vitamin D

      • bisphosphonates

      • Conjugated Estrogen-progestin hormone replacement (HRT)

      • Estrogen-only replacement (ERT)

      • Salmon calcitonin (Fortical or Miacalcin)

      • Raloxifene (Evista)

      • Teriparatide (Forteo)

• Operative

  • osteoporotic vertebral compression fracture

    

  • femoral neck fracture

  • distal radius fracture

Pharmacologic Agents

• Bisphosphonates

  • 1st line therapy

  • indications for pharmacologic treatment

    • hip or vertebral fracture

    • T-score <2.5 at the femoral neck or spine (after exclusion of secondary causes)

    • low bone mass (T-score between -1.0 and -2.5) and

      • 10-year probability of a hip fracture ≥ 3% or greater or

      • 10-year probability of a major osteoporosis-related fracture ≥ 20% based on WHO algorithm/FRAX

  • mechanism

    • accumulate at sites of bone remodeling and are incorporated into bone matrix

    • are released into acid environment once bone is resorbed, and are then taken up by osteoclasts

    • decrease osteoclastic bone resorption, flattening of osteoclast ruffled border and increased osteoclast apoptosis

    • renal excretion without undergoing metabolism

    • exact mechanism depends on presence of nitrogen on alkyl chain (see table below)

  • technique

    • improved rates of treatment when coordinated by treating orthopedic surgeon and referral to osteoporosis clinic is made

    • DEXA scan and referral to endocrinologist

  • outcomes

    • alendronate reduces the rate of hip, spine, and wrist fractures by 50%

    • risedronate reduces vertebral and nonvertebral fractures by 40% (each) over 3 years

    • IV zoledronic acid reduces the rate of spine fractures by 70% and hip fractures by 40% over 3 years

• Osteoporosis medications
  Drug	Indications	Mechanism	Effects	Characteristics	Contraindications/ Adverse Effects
  Calcium & Vit D	Prophylactic in all patients, best for Type II (senile)		Calcium reduces fracture risk by 34%. Vit D supplementation reduces hip fracture risk by 10% and nonvertebral fracture risk by 7%. High dose vitamin D (median, 800IU/d) reduces hip fractures by 24% and nonvertebral fractures by 30%	Daily calcium requirements are as follows: -Age 1-3yrs - 500mg/d -Age 4-8yrs - 800mg/d -Age 9-18yrs - 1000 to 1500mg/d -Age >50 yrs- 1200 to 1500 mg/d Vitamin D requirement is 800-1,000 IUs
  Non-nitrogen-containing bisphosphonates	T score <-2.5SD, fragility fracture of the hip, in both men and women	Produce toxic ATP analog		Etidronate, Clodronate, Tiludronate	Esophagitis, dysphagia, gastric ulcers, osteonecrosis of the jaw (ONJ), atypical subtrochanteric fractures
  Nitrogen-containing bisphosphonates	T score <-2.5SD, fragility fracture of the hip, in both men and women	Inhibit farnesyl pyrophosphate synthase (mevalonate pathway)	Alendronate reduces vertebral fractures by 48% and nonvertebral fractures by 47%. Risedronate reduces vertebral fractures by 65% and nonvertebral fractures by 39%. Ibrandronate reduces vetebral fracture risk by 77%, hip fractures by 41%, and nonvertebral fractures by 15%.	Pamidronate, Alendronate (Fosamax), Risedronate (Actonel), Zolendronate (Reclast), Ibandronate (Boniva)	Esophagitis, dysphagia, gastric ulcers, ONJ, atypical subtrochanteric fractures
  Conjugated Estrogen-progestin hormone replacement	In women with Type I (within 6 years of menopause)				Decreases the risk of hip fracture, but it also led to small increases in a woman's risk of breast cancer, CAD and heart attack, stroke, PE, DVT, and Alzheimer's disease
  Estrogen-only replacement	Indicated for women with prior hysterectomy			Estrogen receptors are present on osteoblasts and osteoclasts	Taking unconjugated estrogen (alone) increases the risk of endometrial hyperplasia / uterine cancer)
  Testosterone	Men with low levels of testosterone			Not yet approved by FDA for osteoporosis
  Salmon calcitonin (Fortical or Miacalcin)	Women >5y postmenopause, decreases pain in acute vertebral compression fractures (acts as a neurotransmitter)	Binds membrane receptors on osteoclasts to inhibit resorption		Injection or nasal spray (destroyed by gastric acid)	Intranasal - Transient rhinitis. Injectable - nausea, vomiting, flushing, hypersensitivity reactions
  Raloxifene (Evista)	Women	Agonist on estrogen receptors in bone (reduce osteoclast resorption). Antagonizes estrogen receptor in breast, reducing breast cancer risk.		Selective estrogen receptor modulator (SERM), slows bone resorption, and mild increase in bone thickness. Reduces risk of vertebral fractures only (not non-vertebral fractures)	Hot flashes, leg cramps. Contraindicated in patients with VTE
  Teriparatide (Forteo)	Severe osteoporosis/high fracture risk	Receptors on osteoblasts (activates osteoblasts) and renal tubule cells, also stimulates intestinal absorption Ca and PO4		1-34 amino-terminal residues of parathyroid hormone (1-84) ;given by daily subcutaneous injections (continuous infusion leads to bone resorption)	Transient hypercalcemia, dizziness, nausea, headache.  Contraindicated in Paget's disease due to potential osteosarcoma risk
  Denosumab (Prolia)	Postmenopausal women at high risk of fracture	Monoclonal Ig2 against RANKL (inhibits binding of RANKL to RANK, like osteoprotegerin)	Reduced vertebral fractures by 68%, hip fractures by 40%, nonvertebral fractures by 20%.	SC injection to arm, thigh, abdomen	Arthralgia, nasopharyngitis, back pain, osteonecrosis of the jaw  Contraindicated in severe hypocalcemia
  Romosozumab (Evenity)	Postmenopausal women with history of osteoporotic fracture, multiple risk factors for fracture, or who have failed or are intolerant to other osteoporosis therapy	Humanized monoclonal Ig2 that activates Wnt pathway by binding sclerostin (sclerostin normally inhibits Wnt pathway). Promotes bone formation and inhibits resorption.	Reduced new vertebral fracture by 73% through month 12 and by 75% through month 24	SC monthly injections	Hyperostosis, cardiovascular events, osteoarthritis, and cancer, osteonecrosis of the jaw, atypical femoral fracture

Complications

• Osteonecrosis of the jaw (ONJ) is associated with IV bisphosphonates (but not oral bisphosphonates)

  • incidence

    • rare

  • treatment

    • stop inciting medication such as a bisphosphonate or Denosumab

• Atypical subtrochanteric transverse stress fractures (in patients on long-term bisphosphonates)

  • incidence

    • rare

  • mechanism

    • extremely low bone turnover rates

    • shown by reduced markers of bone resorption (e.g. urinary collagen type 1 cross-linked N-telopeptide, NTx)

  • treatment

    • operative fixation with an intramedullary nail and stop bisphosphonates

      • Drug holidays are contraindicated in patients with worsening BMD or on chronic corticosteroids 

Prognosis

• Prior fragility fracture is the strongest predictor of a future fracture from low energy trauma

• Vertebral fractures

  • associated with 15% increase in 5-year mortality

  • associated with increased morbidity

    • back pain

    • loss of height

    • poor balance

    • respiratory compromise

      • restrictive lung disease

      • pneumonia

  • history of 1 vertebral fracture results in 5 fold increased risk of 2nd vertebral fracture and 5 fold increased risk of hip fracture

  • history of 2 vertebral fractures is the strongest indicated for further compression fractures in postmenopausal women

• Hip fractures

  • associated with 20% increase in mortality

    • men have higher mortality rates following hip fractures than women

  • associated with increased morbidity

    • reduced quality of life

    • only one-third of patients with hip fractures return to their previous level of function

  • history of 1 hip fracture results in up to 10 fold increased risk of 2nd hip fracture

• FRAX score

  • WHO fracture risk assessment tool that calculates the 10-year risk of hip fracture and 10-year risk of major osteoporosis-related fractures

  • factors include age, sex, personal history of fracture, low BMI, oral steroid use, secondary osteoporosis, parental history of hip fracture, smoking status and alcohol intake