Osteoporosis
consequences of osteoporosis
- "fragility fractures" or "low trauma fractures" - 1 in 2 women and 1 in 4 men > age 50 will have an osteoporosis-related fracture in her/his remaining lifetime - fractures lead to more fractures: every baseline vertebral fracture --> 2-4 fold increase risk for a new hip or vertebral fracture
institute of medicine vitamin D recommendations
- 19-50 years: 600 units - 51-70 years: 600 units - >70 years: 800 units - maximum daily intake: 4000 units
roles in therapy for postmenopausal osteoporosis
- 1st line: alendronate, risendronate, zoledronic acid, denosumab - 2nd line: ibandronate (lack of hip fracture data) - 2nd or 3rd line: teriparatide, abaloparatide (mostly due to cost) - 2nd or 3rd line: raloxifene - last line: calcitonin
vertebral fractures
- 2/3 asymptomatic, 1/3 symptomatic - consequences: pain, spinal deformity, respiratory and GI complications, decreased QOL & ability to do ADLs, increase in depression/fear/anxiety, 2-6 fold increase for mortality (men > women)
trabecular (cancellous) bone
- 20% of the skeleton - found mostly in the axial skeleton (vertebrae) & ends of long bone - composed of interconnecting vertical & horizontal plates giving a honeycomb-like shape - large surface area & is very metabolically active - designed for compressive loads
denosumab dosing and adverse effects/precautions
- 60 mg sq injection every 6 monhts; plus calcium 1000 mg once daily and at least 400 IU vitamin D once daily - given by provider - adverse effects: back pain, arthralgia's, cystitis, flatulence, possible small increase in serious infection - usually at or around the injection site & eczema - precautions/CI: serious infections, dermatologic reactions, ONJ, atypical fractures; do not use if hypocalcemic or pregnant
abaloparatide dosing
- 80 mcg sq injection once daily into the periumbilical region - at this time, only approved for postmenopausal osteoporosis; label limits use to 2 years - store refrigerated at 36-46F *up until use* - after first use, store up to 30 days at room temperature
cortical (compact) bone
- 80% of the skeleton - found mostly in the appendicular skeleton or long bones - cylindrical shaped to withstand bending, torsional and compressive loads
NOF vitamin D recommendations
- <50 years: 400-800 units - >/= 50 years: 800-1000 units - maximum daily intake: 4000 units
propensity to fall
- >90% of hip fractures are due to a simple fall - 33-50% of seniors fall each year - up to 5% of falls lead to fractures - seniors fall more often due to: impaired vision, decrease muscle strength and agility, increase medication % disease states that impair cognition & balance - seniors tend to fall backwards & to the side
central DXA results
- BMD = gm/cm^2 (Ca++ hydroxyapatite) - T-score = represents # of standard (SD) below or above the mean BMD for a healthy, sex-matched, young adult (20-29 yrs) reference population (does not need to be race/ethnicity matched) - Z-score = represents # of SDs below or above the mean BMD for an age, sex and race-matched reference population
calcitonin
- MOA: endogenous hormone released from thyroid glands when Ca is elevated; directly inhibits osteoclast bone resorption - dose: 1 spray intranasal once daily (alternate nares) - adverse effects: nasal irritation and dryness, epistaxis - precautions/CI: increased risk of malignancy (haven't determined causation) - lack of efficacy data outside of vertebral fracture; may provide pain relief in patients with acute vertebral fractures
diagnosis of osteoporosis (T-score)
- T-score at or above -1 (SD) = normal - T-score between -1.0 & -2.5 (SD) = osteopenia (low bone mass) - T-score at or below -2.5 (SD) = osteoporosis - T-score at or below -2.5 (SD) + >/= 1 fracture = severe or established osteoporosis
diagnosis of osteoporosis (Z-score)
- Z-score above -2.0 (SD) = "within the expected range for age" - Z-score at or below -2.0 (SD) = "low bone mineral density for chronological age" or "below the expected range for age" - these criteria are never used along to diagnose osteoporosis in these populations
goal of bone remodeling
- adjust to mechanical strain - repair damage (can take up to 6 months) - provide access to mineral stores
calcium intake recommendations
- age 19-50 years: 1000 mg - age 50-70 years: men = 1000 mg, women = 1200 mg - age >/= 71 years: 1200 mg - maximum daily intake: 2000 mg
bisphosphonate dosing
- alendronate (most often used): PO daily or 70 mg once weekly (recommended) - risendronate: PO daily or 35 mg once weekly or 150 mg monthly - ibandronate: 150 mg PO once monthly - zoledronic acid: 5 mg IV infusion given over at least 15 minutes once yearly at an infusion center (IV only)
hip fractures
- all patients require hospitalization and usually surgical repair (~30% require long term care) - <20% return to pre-fracture function; 15% walk unaided at 6 months - ~20% of women and 30% of men will die within 12 months after
who should be *screened* with QUS
- all postmenopausal women - men >/= 65 years - currently NOT recommended for younger men, premenopausal women, or patients with a suspected secondary cause for bone loss (should be sent for central DXA) - not for patients already diagnosed with osteoporosis/osteopenia: not effective at monitoring response to therapy
age as a risk factor
- all postmenopausal women and men >50 years should be evaluated for osteoporosis risk in order to determine the need for BMD testing and/or vertebral testing
anti-resorptive drug therapies
- alter osteoclasts activity, numbers, or lifespan leading to inhibition of bone resorption - bisphosphonates (most commonly used), denosumab, raloxifene, calcitonin
fall-prevention strategies
- avoid unnecessary medications that can increase fall risk (medications with risk of orthostatic hypotension or dizziness) - evaluate home and personal safety
osteoblasts (B = builders)
- bone building cells - secrete collagen & other bone matrix proteins - promote bone mineralization - emit RANKL which stimulates osteoclast activity
management of osteoporosis
- bone healthy lifestyle (all patients) - adequate calcium and vitamin D intake (all patients) - FDA-indicated drug therapies (selected patients)
possible consequences of inadequate vitamin D
- bone loss --> fractures: decreased calcium absorption & increased parathyroid hormone --> decreased mineralization and increased turnover of bone - falls --> fractures (separate of osteoporosis); impaired neurological and muscle function - possible increase in heart disease and diabetes risk, autoimmune diseases and infection risk, selected cancers
increase loss of bone mass
- bone mass begins to decrease in the 4th decade of life (30s); 0.5% per year - perimenopause & up to 5-7 yrs post-menopause: loss increases to 3-5% per year with drop in estrogen; women > men - elderly: lose ~0.5-1% per year - factors that can accelerate bone loss: similar to those that impact peak mass
osteoclasts (C = construction)
- bone-resorbing cells - remove old or damaged bone
oral bisphosphonate adverse events/precautions
- common: abdominal pain, nausea, dyspepsia - rare: dysphagia; esophageal ulceration; bone, joint, muscle pain; ONJ; atypical femur fractures - *do not use if CrCl <35 mL/min (<30 for risendronate)*, hypocalcemia or esophageal stricture or achalasia
IV bisphosphonate adverse events/precautions
- common: flu-like symptoms (lasts 24-72 hrs); most common with first dose and incidence decreases thereafter (pre-medicate with APAP) - rare: bone, joint, muscle pain; ONJ; atypical femur fractures; renal failure - *do not use if CrCl <30-35 mL/min* or evidence of AKI; do not use in patients at risk for AKI or with hypocalcemia
calcium carbonate
- contains highest amount of elemental calcium (40%) - inexpensive - many different formulations - acid needed for maximal absorption - best if taken with food (more acidic stomach) - possibly more GI intolerance (constipation)
clinical risk factors included in the FRAX tool
- current age - gender - prior osteoporotic fracture: including clinical and asymptomatic vertebral fractures - femoral neck BMD - low body mass index - oral glucocorticoids >5 mg/dose of prednisone for >3 months (ever) - rheumatoid arthritis - current smoking - causes for secondary osteoporosis - parental history of hip fracture - alcohol intake (3 or more drinks/day)
combination therapy (antiresponsive + anabolic)
- data conflicting: studies evaluation concurrent & sequential use, newer data showing combination may be beneficial - benefits need to outweigh risk of increased cost, non-adherence, and adverse effects - no fracture data - cannot be recommended at this time
25-OH vitamin D levels for the general population
- deficient: <12 ng/mL - insufficient: 12-19 ng/mL - sufficient/normal: 20-50 ng/mL
25-OH vitamin D levels for patients at risk for osteoporosis or who have osteoporosis
- deficient: <20 ng/mL - insufficient: 20-29 ng/mL - sufficient/normal: 30-60 ng/mL
drug holiday recommendations
- discontinue after 3-5 years in low risk patients: young, no fracture history, BMD approaching normal - continue in patients at increased risk for fracture: older (>70 in men and post-menopause in women) with a history of fracture and a BMD remaining in the osteoporotic range - patients who many benefit most from continuation: BMD T-score at the femoral neck below -2.5 after 3-5 years of therapy, existing vertebral fracture and BMD T-score < -2.0
teriparatide dosing
- dose: 20 mcg sq injection once daily - label limits use to 2 years (max) - requires special storage instructions and patient education for administration - inject daily into abdomen or thigh, must be discarded 28 days after first use, store refrigerated at 36-46F *at all times*, special airline travel issues
central bone density testing
- dual energy x-ray absorption (DXA) - gold standard: due to its high precision, short scan times (~10 minutes), low radiation dose (<chest x-ray) - uses bone absorption of radiation to determine BMD of the spine, hip, and total body - best predictor of fracture risk - *used for diagnosis & monitoring response to drug therapy*
risk factors for vitamin D deficiency
- elderly: reduced skin conversion, decreased dietary vitamin D absorption - obese individuals: possible sequestration of vitamin D in adipose tissue - dark skin individuals: melanin blocks skin conversion - patients with fat malabsorption: e.g., IBD, Celiac, chronic pancreatitis - patients on certain medications: inducing drugs that accelerate vitamin D clearance (e.g., rifampin, phenytoin) - evidence that these populations (minus the elderly) may require higher doses to reach and be maintained within the sufficient range
disease state secondary causes of osteoporosis
- endocrine: insulin-dependent diabetes, thyrotoxicosis - rheumatologic: rheumatoid arthritis - hypogonadal states: hypogonadism - others: chronic liver or kidney disease
vitamin D deficiency
- ergocalciferol (D2): Rx only - 50,000 units po once to twice weekly for 8-12 weeks - once level is in sufficient range, can give maintenance dose
repletion for vitamin D deficiency
- ergocalciferol (vitamin D2) 50,000 units po once to twice weekly for 8-12 weeks - once level is within the sufficient range can give a maintenance dose (up to 2000 units daily or higher if needed)
assessment of osteoporosis risk factors
- evaluation of risk factors - identify possible signs/symptoms - evaluate for the presence of a secondary cause - bone mineral density testing (bone densitometry)
calcium supplement tips
- give in divided doses (max absorption = 600 mg elemental calcium at a time) - know the salt form - be aware of drug interactions - try to use "USP Verified" - adverse effects: GI upset, bloating or gas, constipation, increased risk for kidney stones with high supplement intake
medications as secondary causes
- glucocorticoids (>/= 5 mg/day prednisone or equivalent for >/= 3 months) - proton pump inhibitors - emerging evidence with SGLT2 inhibitors (canagliflozin - fractures)
teriparatide adverse effects and monitoring
- hypercalcemia & hypercalciuria, orthostasis, dizziness, leg cramps, arthralgias, nausea, pain - black box warning: do not use in patients with increased risk of osteosarcoma - monitoring: serum calcium, urinary calcium (in patients with suspected active urolithiasis or preexisting hypercalciuria, bone mineral density
abaloparatide adverse effects and monitoring
- hypercalcemia & hypercalciuria, orthostasis, dizziness, nausea, HA, palpitations, fatigue, upper abdominal pain - black box warning: do not use in patients with increased risk of osteosarcoma - monitoring: serum calcium, urinary calcium (in patients suspected urolithiasis or preexisting hypercalciuria), bone mineral density
vertebral imaging recommendations
- if BMD T-score at the spine, total hip or femoral neck is =/< -1.0 --> all women age >70, all men >80 yrs old - if BMD T-score at the spine, total hip or femoral neck is =/< -1.5 --> women ages 65-69, men ages 70-79 - postmenopausal women and men >50 with specific risk factors: low trauma fracture during adulthood (age >50), historical height loss of 1.5 inches or more, prospective height loss of 0.8 inches or more, recent or ongoing long term glucocorticoid treatment
bisphosphonate MOA
- incorporated into bone - osteoclasts expose and uptake BPs during resorption - BPs inhibit important osteoclast proteins, resulting in osteoclast apoptosis or inactivity (inhibit OC bone resorption by impairing OC from forming ruffled border as well as decreasing OC development) - alendronate, risendronate, ibandronate, zoledronic acid
anabolic agents
- increase bone formation, bone remodeling rate, and osteoblast number and activity - teriparatide, abaloparatide
calcium
- intake should be obtained ideally through dietary sources - if dietary intake is inadequate, may supplement with oral calcium formulations
calcium citrate
- less elemental calcium (21%) - potentially more expensive - less formulation options - does not need acid for absorption: can be taken with or without food, may be beneficial for elderly patients and patients taking H2RA or PPI - possibly less GI upset
bone-healthy lifestyle
- limit alcohol intake: =/< 1 serving/day for women, =/< 2 servings/day for men - limit caffeine intake: no more than 2-4 servings/day - smoking cessation: current smoking is a major independent risk factor for fracture
other risk factors for osteoporosis
- low calcium intake, vitamin D insufficiency, inadequate physical activity, past history of smoking, falling, high salt intake
atypical fractures
- low trauma subtrochanteric femur fracture; typically transvere or oblique, "stress fracture" - often bilateral - patients frequently experience prodromal thigh or groin pain prior to fracture - causal relationship has not been established for bisphosphonates and denosumab
vitamin D insufficiency
- maintenance dose: cholicalciferol 1000-2000 units po daily; available OTC - some patients may require more depending on specific patient factors
suboptimal peak bone mass
- maximum bone density: 90% by age 18, completed by early 30s - genetics: accounts for 60-80% of the variability in peak bone mass - other factors: inadequate exercise, adverse lifestyle practices (e.g., smoking), disease states/medication, inadequate nutrition, sex hormone deficiency
postmenopausal osteoporosis
- menopause --> decrease in estrogen --> increase osteoclastic activity --> "high turnover" bone loss - can lose up to 10-25% in the 1st decade after menopause and 8-12% each decade after - trabecular bone affected most: leads to increased wrist and vertebral fractures
BMD & therapy recommendations
- normal bone density (T-score > -1.0): no pharmacologic therapy - low bone mass/osteopenia (T-score -1.0 to -2.5): need patient's FRAX score to determine - osteoporosis: (T-score < -2.5)
testosterone replacement
- not FDA-indicated for osteoporosis - suggest testosterone therapy alone in symptomatic hypogonadal men at modest or borderline high risk for fracture - if a man is at high risk for fractures, recommend use of an FDA indicated therapy for treating the osteoporosis
hormone therapy
- not FDA-indicated for the treatment of osteoporosis - can use short-term for the prevention of osteoporosis in women with menopausal symptoms and risk for bone loss
age-related osteoporosis
- occur in older individuals (>70) - female:male = 2:1 - due to: decrease in intestinal calcium absorption, decrease in sex hormone production, decrease in osteoblastic/osteocyte activity - equal effect on cortical & trabecular bone: increase risk in all fracture types (especially hip)
drug holiday recommendations for patients with moderately increased risk
- older, T-score below -2.5, no fractures, some risk factors - treat 5-10 years - stop for 2-3 years or until significant decrease in BMD or fracture
drug holiday recommendations for high risk patients
- older, very low BMD, multiple risks or fractures - treat 10 years - stop for 1-2 years or until significant decrease in BMD or fracture; possibly use alternate med during drug holiday
osteoporosis drug holiday
- only possible with *bisphosphonates* due to long bone retention - bone retention differs between bisphosphonates, best data with alendronate and zoledronic acid, no data with ibandronate - limited data shows some continued bone benefit (BMD and fractures) after drugs are stopped
pharmacist's role
- peripheral bone density screenings - recommend appropriate pharmacotherapeutic management based on BMD results & risk factors (FRAX score) - review patient records for medications that increase fall risk - patient counseling: osteoporosis medications (risks/benefits, administration issues), bone-healthy lifestyle, adequate calcium and vitamin D intake
when to consider drug treatment
- postmenopausal women and men >/= 50 years of age and one of the following risk factors: - history of hip or vertebral fracture - T-score < -2.5 at femoral neck, hip or spine by central DXA - T-score between -1 and -2.5 and 10-year hip fracture probability of >3% OR 10-yr all major osteoporosis-related fracture probability of >20%
roles in therapy for glucocorticoid induced osteoporosis
- postmenopausal women and men >50 years: drug therapy recommendations are based on risk category using FRAX, and dose/duration of steroids - premenopausal women and men <50 yrs: inadequate data to recommend therapy for patients without a prevalent fragility fracture, drug therapy recommendations for patients with prevalent fragility fracture based on child-bearing potential, dose and duration of steroid - recommended agents: alendronate, risendronate, zoledronic acid, teriparatide (second line)
goals of management
- prevention: optimize skeletal development and peak bone mass accrual in childhood, adolescence and early adulthood; prevent excessive bone loss - treatment: stabilize or improve bone mass and strength, prevent fractures, improve functional capacity and quality of life
classification of osteoporosis
- primary: postmenopausal, age-related, idiopathic (men) - secondary: disease related, drug related
osteonecrosis of the jaw
- progressive destruction and death of bone that affects the mandible or maxilla - >90% of cases have occurred in patients receiving high dose IV bisphosphonates for cancer - prevalence estimates in patient without cancer range from 0.001%-0.10% - risk increases with longer duration of use - cases have been reported with bisphosphonates (PO & IV) used for osteoporosis and denosumab
peripheral bone density scanning
- quantitative ultrasound (QUS) of heel: estimates BMD using sound waves; less expensive than central bone density testing, easy to use, safe with no radiation exposure, portable - used for screening: *NOT* diagnosis or monitoring - can help with risk assessment - predicts fracture risk - other: peripheral DXA (dual energy x-ray absorptiometry) of the finger, forearm, heel - uses radiation
estrogen agonist/antagonists (EAAs)
- raloxifene - conjugated estrogens/bazedoxifene (Duavee)
estrogen agonist/antagonist dosing and adverse effects/precautions
- raloxifene: 60 mg po once daily - CE/bazedoxifene: CE 0.45 mg/bazedoxifene 20 mg daily; only for use in patients with an intact uterus - adverse effects: hot flashes, leg cramps, peripheral edema, 3 fold increase risk for VTE - precautions: small increase risk for fatal stroke (raloxifene); do not use in patients >75 years old (CE/bazedoxifene) - CI if history of VTE (black box warning)
estrogen agonist/antagonists MOA
- raloxifene: selective estrogen receptor modulator - Duavee: second generation mixed estrogen agonist/antagonist; estrogenic actions in bone, estrogenic antagonist actions in breast and uterine tissue - the effect of estrogen is to upregulate OPG and down regular RANK-L --> reduced formation of osteoclasts, increase in osteoclast apoptosis
anabolic agents MOA
- recombinant human PTH - exogenous PTH in low and intermittent doses increases bone formation without stimulating bone resorption as endogenous PTH does - increases bone remodeling - increases osteoblast number and activity
BMD frequency for those indicated
- repeat 1-2 years after initiation of medical therapy, then every 2 years
ONJ FDA labeling
- routine dental exams prior to & during therapy - dental exam with appropriate preventative dentistry in high risk patients prior to initiation - complete any major dental procedures before initiation or avoid if possible - if dental procedures during therapy: no data that discontinuation decreases risk, use clinical judgement based on benefits/risk
secondary osteoporosis
- secondary causes are accountable in: >50% of premenopausal women; ~1/3 of postmenopausal women (often goes undetected); 2/3 of men - due to: disease state, medications - affects: women, men; all ages; all ethnic groups and racial backgrounds
bisphosphonate monitoring
- serum calcium at baseline - dental examination at baseline - adherence and administration: BPs and calcium/vitamin D supplementation - renal function (SCr) - bone mineral density: DXA is gold standard for serial assessment; generally, every 2 years
denosumab monitoring
- serum calcium, phosphorus and magnesium (at baseline, then periodically) - dental exam (at baseline, then periodically) - calcium and vitamin D intake - pregnancy test in women of childbearing age - bone mineral density: DXA; generally, every 2 years; medical necessity exceptions
EAA monitoring
- signs/symptoms of VTE (blood clots): discontinue use if a patient anticipates extended immobility - pregnancy testing if childbearing age - bone mineral density
RANKL (receptor activator of nuclear kappa B ligand)
- stimulated by PTH, TGF-B, PGE2, TNF-a --> bone resorption - inhibited by estrogen, testosterone, calcitonin (active vitamin D) --> bone formation - inhibited by osteoprotegerin (OPG)
efficacy in men
- studies are smaller and of a shorter duration - similar increases in BMD - less data regarding fracture reduction - most data with zoledronic acid
vitamin D
- sunlight (UVB) --> endogenous: main source; affected by season, latitude, age, skin, pigmentation, sunscreen use - dietary: minor source; fatty fish and fortified foods (milk, cereal) - supplements: alone, in combination with calcium, and in multivitamins
signs and symptoms of osteoporosis
- symptoms: low bone mass is asymptomatic, possible subtle low back pain with a vertebral fracture - signs: loss of height >1.5 inches; kyphosis, lordosis; low bone density on X-ray, low-trauma fracture (not fingers, toes, or skull)
delayed-release risendronate administration
- take immediately after breakfast with at least 4 oz plain water - do not lie down or take any meds for at least 30 minutes - not recommended in patients taking an H2RA or PPI
oral bisphosphonate administration
- take on an empty stomach, upon rising for the day with a full glass of water (6-8 oz) - do not lie down (leads to GI irritation - esophageal sphincter is relaxed), eat, drink, or take any meds for at least 30 minutes (60 minutes for ibandronate)
disruption of microarchitecture
- trabecular perforations (loss of connectivity) = loss of strength - more difficult to assess bone quality than bone density
possible causes of secondary osteoporosis
- type 1 diabetes - osteogenesis imperfect in adults - untreated long-standing hyperthyroid - hypogonadism - premature menopause (<45) - chronic malnutrition/malabsorption - chronic liver disease
monitoring response to therapy
- use central DXA to monitor response, need to use the same site and same DXA machine (variability amongst machines) - takes 1-2 years to see significant chance - actual BMD value is used to follow the percent change in BMD over time (not T-score) - non-responder = decrease in BMD of greater than the precision of the machine (>3-5% depending on machine) - same BMD does NOT = non-responder
roles in therapy for men
- use therapy FDA-indicated in men - generic alendronate will often be preferred, risendronate is an oral alternative - in men with a recent hip fracture, suggest treatment with zoledronic acid - in men at risk for vertebral fracture, teriparatide may be preferred, although more expensive - choice of therapy should be individualized based on factors such as fracture history, BMD t-scores, risk for hip fracture, co-morbid conditions, and cost
exercise for a bone-healthy lifestyle
- weight bearing (jogging, walking, stair climbing, tennis, etc.): moderate intensity for 30 minutes most days of the week - resistance (free weights, weight machines, resistance bands): twice weekly for 20-30 minutes
BMD testing indications
- women age 65 and older and men age 70 and older, regardless of risk factors - with clinical risk factors for fracture: postmenopausal women, mean age 50-59 - adults who have a fracture after age 50 (non-traumatic) - adults with a condition (e.g. rheumatoid arthritis) or taking medications (e.g. glucocorticoids) associated with low bone mass or bone loss
drug holiday recommendations for mildly increased risk
- younger + T-score just below -2.5 + no additional risk factors or osteopenia with risk factors - treat for ~5 years - stop until significant decrease in BMD or fracture
continuous bone remodelling
a normal process with 1-2 million microscopic areas of bone being repaired at any given time (BMUs)
BMUs
basic multicellular units - small sections of bone undergoing remodeling
denosumab MOA
fully human monoclonal antibody; binds to RANKL, blocking ability to bind to RANK on OC --> increased OC apoptosis
osteoporosis in men
less common due to: - higher peak bone mass - greater bone size/strength - absence of menopause - shorter life expectancy - lower propensity to fall
bone composition
mineral (50-70%) - gives strength & rigidity to bones - mainly calcium hydroxyapatite - 95% calcium stores, 85% phosphate store organic matrix (20-40%) - gives elasticity & flexibility to bones - 90% = type 1 collagen - 10% = non-collagenous proteins and cells
osteoporosis
systemic skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk for fracture
