Osteoporosis Flashcards
Define osteoporosis
- Fragility of bone causing increased risk of fracture
- WHO Classification: BMD T score < -2.5 defined as osteoporosis
Describe the financial burden of osteoporosis
- There will be 2.07 million older people in NSW & ACT with low bone mass, an increase of 26% from 2012
- There will be 174 fractures every day among older people in NSW & ACT. More than one in six of these fractures will be a hip fracture.
- The total costs of osteoporosis and osteopenia in people in NSW & ACT over 50 years of age was $1.1 billion of which $740 million (67%) relates to the treatment of fractures (2017)
Distinguish between osteoporosis, osteopenia and osteomalacia
Osteopenia/Osteoporosis
- Bone matrix normally mineralised but there is less bone (osteopenia not < 2.5)
Osteomalacia
- When there is insufficient Calcium and Phosphate to mineralise newly formed osteoid. Bone is softer and liable to bend, deform or fracture
Matrix Mineral Comparison
- Normal: matrix: mineral
- Osteoporosis: same proportion of mineral and matrix, fewer quantity
- Osteomalacia: changed proportions, less mineral and more matrix
List and briefly describe the two types of osteoporosis
Generalised
- Osteoporosis unassociated with other diseases – Primary Osteoporosis
- Osteoporosis associated with other diseases – Secondary Osteoporosis
Regional
- Transient regional osteoprosis
- Transient osteoporosis of the hip
- Transient migratory osteoporosis
List examples of generalised osteoporosis
- Postmenopausal
- Aging
Bone density declines naturally in these two states.
List examples of osteoporosis associated with other diseases
- Inflammatory Arthritis
- Rheumatoid Arthritis
- Environmental
- Calcium Deficiency
- Alcohol and smoking
- Drug induced – Corticosteroids, Heparin
- Endocrine Causes
- Hyperparathyroidism
- Cushing’s syndrome
- Hyperthyroidism
- Hypogonadism
- Anorexia Nervosa
- Exercise Induced Amenorrhea
How do we go about diagnosing osteoporosis?
- Early diagnosis now possible before fracture occurs
- Osteoporosis is defined in relation to degree to which bone mineral density is reduced
- T score (number of standard deviations from the young normal mean) – used to make diagnosis
- Z score (number of standard deviation from age matched mean) – gives a clue as to whether secondary cause is indicated
- Osteoporosis is defined as T score below –2.5
Describe the types of BMD
- Spine (L1-4 or L2-4)
- Predicts spine fracture
- Useful for monitoring – treatment changes are largest
- Trabecular bone
- Note: Osteophytes can cause falsely high bone density results
- Hip (Femoral neck, intertrochanteric, trochanteric)
- Femoral neck or total hip
- Predictive of fracture risk hip and spine
- Cortical bone
T scores and Z scores
- T score – measured BMD compared with mean value for young healthy population. T score is number of standard deviation below or above this average. Used for diagnosis of osteoporosis
- Z score – the measured BMD (g/cm2) compared with mean value for age and sex and race matched population. Useful to determine if a secondary cause exists for OP
BMD: advantages and disadvantages
BMD
- 1994 benchmark for diagnosis of Osteoporosis
- Good predictor of fracture
- As good as, if not better, than ability to predict heart disease from blood cholesterol and to predict stroke from blood pressure
- Note: severe osteoporosis= -2.5 or less, plus fracture
Bone Mineral Density
Advantages
- Quick and easy
- Minimal radiation exposure
- Widely used in clinical trials
- WHO classification based on DEXA
- Good correlation with risk of fracture
Limitations
- Mineral content across a specific area not taking depth into consideration
- Does not provide full assessment of bone strength (microarchitecture, bone turnover)
- Vary between instruments (therefore do follow-up densities in the same clinic if possible)
Describe FRAX tool
FRAX Tool –WHO Fracture Risk Assessment Tool
- Clinical risk factors as well as bone mineral density (BMD) at the femoral neck.
- FRAX® tool is computer-driven
- FRAX® algorithms give the 10-year probability of fracture. The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture).
- 10 yr probability >20% in MOP and >3% for Hip # - consideration for treatment
- Avoids possibility of overtreating someone with bone density low alone, with low probability of fracture
Describe normal bone development over lifetime
- Increase in BMD till Age ~ 35 yrs
- Influenced by many factors
- Peak Bone Density
- Following this decline occurs
- Influenced by many factors
Peak Bone Mass
- Peak bone mass accrued through Intrauterine growth, childhood, puberty
- Genetic factors determines peak bone mass
- Environmental factors during growth modulate the genetically determined pattern of bone growth
- Subsequent bone loss
Describe bone tissue
- Bone is a dynamic structure
- Constant remodeling: influenced by systemic hormones and local factors (lifestyle, diet, etc)
- bone resorption by osteoclasts (OC)
- bone formation by osteoblasts (OB)
- Bone remodeling facilitates repair of microcracks and provides calcium for bone stores for cellular function
- Metabolic component of bone remodeling – Bone Remodeling Unit (BRU)
- Over 1 million of these are active at any one time in a healthy woman
- Complete turnover of skeleton occurs every 10 years
- Active and dynamic process of bone remodeling allows opportunities for interventions - e.g. at specific sites
Bone: physiology
- Osteoclast
- Osteoblasts
-
Osteocytes
- OC resorption over 3 weeks
- OB activation and bone formation over 3 months
-
Remodelling imbalance
- Resorption cavities deeper and more frequent, resulting in perforations
- Cavities incompletely filled, resulting in…
- Progressive loss of trabecular bone due to increased osteoclastogenesis
Describe OB and OC communication
- Receptor activator of nuclear factor kappa B (NFkB) RANK, RANK ligand system and OPG (Osteoprotegrin) involved in OB-OC communication
- OC maturation dependent on RANK and RANKL interaction (RANKL on OB, stromal cells)
- OPG and RANKL compete. OPG is the decoy, keeps OC stimulation in check
- Estrogen may exert antiresorptive effect on bone by stimulating OPG expression in OB
- Antibodies to RANKL (Denosumab) now available for osteoporosis
Describe regulation of osteoblasts
- LDL receptor – related protein 5 (LRP5) is modulator of OB function.
- Co receptor of series of OB stimulating proteins operating through Wnt signalling pathway.
- Frizzled and LRP5 bind to Wnt, activating bone formation
Describe the role of sclerostin
- Sclerostin antagonizes Wnt signaling by occupying Wnt coreceptors LRP5/6 and preventing their binding to Wnt ligands, which inhibits downstream canonical Wnt signaling.— inhibiting bone formation?
- Sclerostin was originally discovered because of inactivating mutations SOST gene that cause the rare high bone mass disorders sclerosteosis and van Buchem disease
Describe non-pharmacological prevention and management of osteoporosis
Prevention strategies
- Attain Best Peak Bone Density
- Good Calcium Intake
- Exercise
- Avoid smoking, excessive alcohol
- Minimise drugs that can influence BMD adversely
Non-Pharmacological treatment
- Weight Bearing Exercises
- Adequate Calcium 800mg – 1200mg/day
- Vitamin D intake
- Avoid Risk Factors –smoking, alcohol
Briefly describe the pharmacological management of osteoporosis
-
Antiresorptives – 1st line agents
- Bisphosphonates
- SERMS
- RANK Ligand inhibitor
- Calcitriol
-
Anabolic Agents – 2nd line
- Parathyroid Hormone
- Antisclerostin Ab
-
Dual Agents
- Strontium Ralenate
Briefly describe the role of antiresorptives
- Do not ‘build’ bone
- Reduce bone resorption
- Allows more complete secondary remineralisation of existing bone
Describe antiresorptive agents
Bisphosphonates
- First line treatment Alendronate and Risendronate
- Compliance: Weekly medications, Risendronate now monthly, IV Zolendronic Acid – annual infusion
- 50% compliance for orals
- GI side effects can be limiting
- Improvement in bone density and fracture reduction data at vertebral and non vertebral sites
- Recent Concerns of rare problems:
- ONJ (Osteonecrosis of jaw) 1:10,000 – 1:100,000 in patients on treatment for osteoporosis – consult with dentists to avoid infection
- Atypical fractures
Denosumab
- Fully human monoclonal antibody to the receptor activator of RANKL
- Denosumab inhibits osteoclast formation function and survival
- Denosumab is an IgG2 immunoglobulin isotype, which has a long half-life and allows for subcutaneous (SC) injection of this agent every 6 months.
- if not taken within window, increased risk of fractures. Commitment is important. Move patient to a different treatment e.g. bisphosphonates if deno no longer suitable
- Denosumab was associated with a significant reduction in the risk of vertebral, hip, and nonvertebral fractures in postmenopausal women with osteoporosis.
Estrogen
- Bone remodelling accelerated at menopause – remodelling imbalance
- Womens Health Initiative (WHI) – risk of breast cancer significant with HRT not advisable for treatment of osteoporosis.
Antiresorptive Agents - SERM
- SERM (Selective Estrogen Receptor Modulator) Raloxifene
- Acts on estrogen receptors in bone and not in the breast tissue
- Evidence of improved bone density
- Evidence for reduced fracture at vertebral site
Describe the action of PTH
- Parathyroid Hormone (Teriparatide)
- Teriparatide is the portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids).
Parathyroid Hormone - Mechanism of action
- PTH increases serum calcium - by increasing bone resorption.
- Chronically elevated PTH will deplete bone stores.
- Intermittent exposure to PTH - activate osteoblasts more than osteoclasts. - why??
- Once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.
Describe strontium ralenate and romosozumab
Romosozumab
- Sclerostin is produced by osteocytes.
- increase bone resorption and decrease bone formation
- Lack of sclerostin – increase bone density
- Romosozumab monoclonal antibody that binds to sclerostin and inhibits its action
- 2 injections -monthly subcutaneous injections
Dual Agent - Strontium Ralenate
- Strontium Ralenate
- Dissociates bone remodelling – increases bone formation and decreases bone resorption
- Induces preosteoblasts and osteoblasts differentiation
- Inhibits osteoclasts differentiation
Strontium Ralenate
- Reduces the risk of vertebral fractures and non vertebral fractures
- 2gm daily – orally
- Contraindications:
- Hypertension
- PH of CVA, Thrombosis
Describe minimal trauma fractures
Minimal Trauma Fracture
- Minimal Trauma Fracture: Fracture from standing height or no trauma. Regardless of BMD level, a minimal trauma fracture indicates osteoporosis.
- PBS Subsidy
- Secondary Prevention: After minimal trauma fracture. More common
- Primary Prevention: Over 70 yrs and corticosteroid-induced osteoporosis.
Describe how a choice is made for one therapeutic agent over another
Choice of Agents Dependent on Type of Osteoporosis
- Post Menopausal Osteoporosis
- Male Osteoporosis
- Corticosteroid Induced Osteoporosis
- Primary Prevention
Examples:
Choice of Treatment: Primary Prevention
- Corticosteroid Induced Osteoporosis:
- >7.5mg Prednisolone for > 3 mo.
- T score <-1.5.
- Bisphosphonates.
- Osteoporosis – Primary Prevention (T score >-2.5) Without Fracture (Females and Males Over 70yrs):
- Bisphosphonates: Alendronate, Risendronate.
- Denosumab.
