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 decreased loading stress (e.g non-weight-bearing after fracture) 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 Osteoporosis 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