1
Q
What is osteoporosis?
A
A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissues, leading to enhanced bone fragility and a consequent increase in fracture risk
2
Q
How many patients need treatment for osteoporosis?
A
1/3 of elderly population will require treatment
3
Q
What is a fragility fracture?
A
They occur from falls at standing height or when force is applied to the bone judged to be insignificant to fracture a normal bone
4
Q
What are the four major osteoporotic fractures?
A
- Hip
- Vertebra
- Humerus
- Distal forearm
1/3 of women and 1/5 of men will suffer from an osteoporotic fracture
5
Q
What are the mortality rates by sex for hip fractures?
A
28% of women and 33% of men who suffer a hip fracture will die within the following year
6
Q
Are fractures of the hands considered major osteoporotic fractures?
A
No, alongside the feet and craniofacial bones
7
Q
How many patients are affected by osteoporosis?
A
2.3 million Canadians over the age of 40 (women are affected more than men)
8
Q
What are the two types of bone?
A
Cortical
Cancellous
9
Q
What are the characteristics of cortical bone?
A
- 80% of weight of the adult skeleton
- Dense, forms outer shell
10
Q
What are the characteristics of cancellous bone?
A
- 20% of weight of the adult skeleton
- Porous, forms interior structures
11
Q
What are the three types of bone cells?
A
- Osteoblasts (“bone builder”)
- Osteoclasts
- Osteocytes (bone mineralization regulatory functions)
12
Q
What happens when bone remodelling balance becomes negative in favour of osteoclasts?
A
Bone mineral density (BMD) decreases progressively as long as bone remodelling stays in the favour of osteoclasts
13
Q
What does advancing age do to bone remodelling?
A
- Oxidative stress (free radicals and low grade inflammation results in resorption)
- Osteoblasts senescence (halted production of osteoblasts)
- Autophagy delines (quality control)
14
Q
What is the impact of sex steroids on bone remodelling?
A
- Estrogen (due to reduced estrogen in menopause, there is a reduction in BMD)
- Androgens (Men achieve a higher BMD due to the effect of androgens)
15
Q
What is the function of parathyroid hormone in bone remodelling?
A
PTH takes Ca2+ from bone and puts it into the blood
16
Q
What is the function of calcitonin in bone remodelling?
A
Calcitonin pulls Ca2+ from blood to bone (calcitonin = “tone down”)
17
Q
What is the role of Ca2+ in bone remodelling?
A
Ca2+ is required for mineralization of bone
18
Q
What is the role of Vit D in bone remodelling?
A
Vit D helps regulate Ca2+
19
Q
What happens in hypocalcemia?
A
- Parathyroid releases PTH
- PTH stimulates release of Ca2+ and phosphorus (P) from bone and reabsorption of Ca2+ in the kidneys
- Vit D is activated in the kidneys to increase Ca2+, PO4, and Mg absorption by the intestine
- Vit D is also an inhibitor of PTH, closing the negative feedback loop
20
Q
What happens in hypercalcemia?
A
- Calcitonin is released by thyroid
- Calcitonin inhibits intestinal absorption of Ca2+ and phosphorus
- Calcitonin also stimulates Ca2+ excretion in the kidneys
Overall, this pathway attempts to reduce Ca2+ in the blood. Hypercalcemic patients are unlikely to see bone resorption.
21
Q
What happens to osteocytes to cause osteoporosis?
A
Osteocyte death accelerates with age (need mechanical stress to keep osteocytes healthy)
Osteocyte death is linked to the following:
- Increased surface remodelling
- Replacement with weaker mineralized connective tissue
- Disruption in repair signalling
- Decrease in bone vascularity
22
Q
What is the etiology of osteoporosis?
A
After age 35, BMD reaches peak and starts to decline by 0.5% per year (2-3%/year during menopause due to shift in estrogen levels)
Women, on average, lose 50% of trabecular and 35% of cortical bone, while losses experienced by men are 2/3s of what women experience.
23
Q
What is the most common type of fracture due to osteoporosis?
A
Vertebral fractures (contribute to kyphosis) account for 50%, followed by hip and distal forearm fractures
24
Q
What are some risk factors associated with osteoporosis?
A
- Race (Whites and Asians are at increased risk)
- Ca2+ intake during growth
- Age
- Menopause (especially in women with early menopause, under 45)
- Family History (history of hip fractures in older adults)
- Sex (less common in men)
- Small stature (low body weight or fine bone structure)
- Weight (mechanical stress on bones is beneficial for increasing BMD)
- Secondary causes (medical conditions, drugs, lifestyle, previous falls and fractures)
25
What are some medical conditions that increase risk of osteoporosis?
- Oophorectomy (removal of ovaries = less estrogen = reduced BMD)
- Hypogonadism
- Hyperparathyroidism
- Cushing's
- Multiple myeloma
- Malabsorption syndrome
- Chronic inflammatory diseases
26
What are some types of drugs that predispose patients to a higher risk of developing osteoporosis?
- Androgen deprivation therapy (reduce BMD)
- Anticoagulants (heparin, LWMH, warfarin)
- Antidepressants (SSRIs, SNRIs, lithium)
- Antiepileptics (phenytoin, carbemazepine)
- Anti-neoplastics (aromatase inhibitors)
- Antiretrovirals (increase osteoclast activity and reduced osteoblast activity)
- Calcineurin inhibitors (associated with increased osteoclast activity)
- SGLT2i (Canagliflozin)
- **Glucocorticoid therapy**
- Loop diuretics
- Medroxyprogesterone
- PPIs (less acidic = less Ca2+ absorption)
- Thyroid supplementation
- Vit A excess (increased fracture risk)
27
What are some lifestyle risk factors for developing osteoporosis?
- Nutrition
- Exercise (weight-bearing exercise and increase flexibility)
- Alcohol
- Smoking (inhibits estrogen)
- Caffeine
- Sunshine (aids Vit D production)
28
What are some risk factors for falls and fractures?
- Age-related fractures
- Environmental hazards (tripping hazards)
- Drug-falls (psychotropic, antihypertensive)
29
What is the common presentation of osteoporosis?
No symptomatic manifestation until a fracture occurs (broken bone can be painful)
Vertebral fractures are the most common in osteoporosis patients
30
What are some osteoporosis diagnosis criteria?
Vertebral compression fracture, hip fracture, or more than one fragility fracture in patients over 50
31
How are osteoporosis and osteopenia differentiated?
Using a BMD T-score
Osteoporosis: more than -2.5 standard deviations from normal peak
Osteopenia: between -1 and -2.5 standard deviations from normal peak
32
What patient profiles should be screened for osteoporosis?
Men and women (especially post-menopausal) over 50 should begin routine assessment of risk factors for osteoporosis and fracture
If screened and at low risk, retest in 5 years
If moderate risk (and not treating), reassess in 1 to 3 years
33
What are the elements of osteoporosis risk screening?
- Detailed History (identify risk factors for low BMD, future fractures and falls)
- Physical Examination
- Biochemical tests
- BMD in select individuals
- Use of Risk Assessment Tools (CAROC and FRAX)
- Vertebral imaging in selected individuals
34
What are some elements of the physical exam for evaluating osteoporosis risk?
- Measure weight (weight loss of more than 10% since age 25 is significant or total weight below 60kg)
- Measure height annually (prospective loss more than 2cm, and historic loss more than 6cm is indicative of osteoporosis)
- Assess fall risk by using Get-Up-and-Go Test
35
What are some recommended biochemical tests for osteoporosis?
- Calcium, corrected for albumin
- Phosphate
- Creatinine
- ALP (increase bone turnover)
- TSH
- Vit D
36
What is Paget's disease?
It is a disorder in bone remodelling
37
What are the three locations where bone mineral density is reported on a DXA scan?
- Total hip
- Femoral neck
- Lumbar spine
38
What is the most commonly used BMD scale when performing a DXA scan?
T-score is used for adults over 50 who have received a DXA scan
The t-score is measures as number of standard deviations the person's BMD is above or below a control value
39
What patient profiles should get a DXA scan for BMD testing?
Postmenopausal women and men:
- Age 50-64 with previous osteoporotic-related fracture or more than 2 clinical risk factors for fracture
- Age over 65 with one clinical risk factor
- Age over 70, regardless of risk factors
40
What clinical risk factors warrant a DXA scan to get an estimate of BMD?
- Previous fracture (after age 40)
- Glucocorticoids (long-term use)
- Falls (more than 2 in the last year)
- BMI below 20
- Secondary osteoporosis
- Current smoking
- Alcohol use
41
What are the risk assessment tools for osteoporosis?
CAROC (Canadian Association of Radiologists and Osteoporosis Canada)
FRAX (Fracture Risk Assessment Tool developed by the World Health Organization)
42
What are some characteristics of the CAROC score?
- Validated for postmenopausal women and men over 50
- Easier to understand the T-score as determined from DXA score
- Basal risk category is based from age, sex, and T-score from the femoral neck alone (discard readings from other sites)
43
What are some characteristics of the FRAX score?
It computes the 10-year probability of hip fracture and major fracture probability
- Incorporates more factors than CAROC (prior fracture, prolonged corticosteroid use, etc.)
- Canadian specific FRAX is the preferred tool
- Can be used without BMD (less accurate though)
44
What are some limitations of risk assessment scores used in osteoporosis?
- Calculate risk for treatment-naive patients only
- Cannot be used to monitor response to therapy
- May underestimate risk in the presence of specific factors (recurrent falls, low BMD at non-femoral neck sites)
45
Besides the DXA scan, what are some alternative methods of determining BMD and osteoporotic risk?
Qualitative ultrasound
Bone turnover markers (ex. urinary C-terminal telopeptide, needs more research to be used reliably)
46
How often should BMD testing be completed according to FRAX scores?
10-year fracture risk over 15% or on pharmacotherapy: In 3 years
10-year fracture risk between 10 and 15%: In 5 years
10-year fracture risk less than 10%: In 5 to 10 years
May need to repeat earlier if secondary causes of osteoporosis, new fractures or new clinical risk factors associated with rapid bone loss
47
What are the goals of treatment for osteoporosis?
- Prevent fractures
- Prevent disability and loss of independence
- Preserve or improve BMD
- Reduce modifiable risk factors
48
What are the types of pharmacological agents used to treat osteoporosis?
1st line:
- Bisphosphonates
- Denosumab
2nd line:
- Raloxifene
- Teriparatide
- Hormone Therapy
49
What are the advantages of exercise in osteoporosis therapy?
- Stimulates osteoblast activity
- Improves QOL, physical function, pain, strength and balance
Encourage a variety of types and intensities, but prioritize balance, functional and resistance training more than 2 times weekly
50
What are some balance exercises?
- Shifting body weight to the limits of stability
- Reacting to things that upset your balance (catching and throwing a ball)
- Maintaining balance while moving (ex. Tai Chi, heel raises)
- Reducing base of support (standing on one foot)
51
What are some functional exercises?
Exercises that improve the ability to perform everyday tasks or do activities for fun or fitness
These exercises ultimately prevent injuries
52
What is resistance training?
Exercises where major muscle groups (upper and lower extremities, chest, shoulders, back) work against resistance
ex. Squats, lunges, and push-ups
Many resistance training exercises can be considered functional exercises
53
What are some measures that can help prevent falls?
- Patient education
- Home safety assessments
- Hip protectors
- Bars, canes, walkers, etc.
- Remove tripping hazards
- Improve balance and strength
- Avoid drugs associated with increased fall risk (many drugs on BEERS list)
54
What is the impact of smoking on BMD?
- 1-pack-per-day history leads to approximately 10% reduction in BMD
Negates the protective effect of HRT (estrogen replacement) in women
55
What is the impact of alcohol consumption on BMD?
More than 4 drinks per day may lower BMD by 4%
56
Is oversupplementation of Ca2+ reccomended for prevention of fractures?
No, oversupplementation of Ca2+ does not reduce fracture risk on its own
57
What are the RDAs for Ca2+ in older adults?
Men:
- 50-70 yo: 1000mg/day
- More than 70yo: 1200mg/day
Women:
- Over 50yo: 1200mg/day
58
What are the different types of calcium salt supplements and how much elemental Ca2+ do they contain?
- Calcium carbonate: 40%
- Calcium citrate: 21%
- Calcium lactate: 13%
- Calcium gluconate: 9%
59
What are some non-traditional calcium supplements?
- Bone meal (not reccomended by pharmacists)
- Dolomite
- Chelated calcium
- Oyster shell (can contain Pb)
60
What are some drug interactions associated with calcium supplementation?
- PPIs reduce absoroption of Ca2+
- Decreased absorption of cipro, iron, protease inhibitors, tetracycline, thyroid medications
61
If the patient is on a PPI, what is the best type of calcium supplementation?
Calcium citrate is best
Can also be used in patients that want to take their Ca2+ supplement without food
62
Can the entire daily RDA of calcium be taken in one administration for best efficacy?
No, it is best that the daily Ca2+ supplementation is taken in 2 doses (best absorption occurs for doses below 550mg of elemental Ca2+)
63
What are the concerns of oversupplementation of Ca2+ (more than 2000mg/day)?
- Nephrolithiasis
- CV disease
- Dyspepsia
- Constipation
64
What is the RDA for Vitamin D?
Men and women:
- Under 70: 600 IU vitamin D/day
- Over 70: 800 IU vitamin D/day
65
What is the preferred Vitamin D supplement form?
Cholecalciferol
66
What are some natural sources of Vitamin D?
Few food sources
- Fatty fish (salmon, rainbow trout)
- Fortified foods (cow milk, plant-based beverages)
- Eggs
- Sun exposure
67
Is Vitamin D level monitoring done commonly in osteoporotic patients?
No, it is not necessary in most patients (expensive)
If we are monitoring Vit D, do not retest until 3 months after supplementation
68
What are the ideal Vitamin D levels for good bone health in healthy individuals?
Between 50 and 125 nmoL/L
69
What are antiresorptive therapeutic agents used in osteoporosis?
Prevent break down of bone
- Bisphosphonates
- Denosumab
- Raloxifene
- Hormone Therapy
70
What are the anabolic therapeutic agents used in osteoporosis?
Help build bone
- Teriparatide
- Romosozumab
- Combination therapy
71
When should pharmacological treatment for osteoporosis be initiated?
Low risk (T-score less than 15%)
Intermediate risk (T-score between 15 and 30%)
High risk (T-score more than 20%)
72
What are the first-line treatments for osteoporosis?
Bisphosphonates and denosumab
73
What is the recommended treatment for osteoporosis in patients that have had a recent severe vertebral fracture (in the last 2 years)?
Teraparatide or Rosmosumab + Bisphosphonate
74
How often should patients on osteoporosis therapy have their BMD tested?
3 years
A shorter retesting interval may be appropriate for those with secondary osteoporosis
75
What is the effect of bisphosponate therapy in osteoporosis?
Halts BMD decline and slightly reverses loss
Fracture risk decreases are independent of BMD changes (2-6% increase in BMD, but 40-60% reduction in fracture risk)
76
What are some indications for bisphosphonates?
- Postmenopausal osteoporosis treatment and prevention
- Osteoporosis in men
- Treatment and prevention of glucocorticoid-induced osteoporosis
- Paget's disease
77
What are some examples of bisphosphonates?
- Alendronate
- Risedronate
- Zoledronic Acid (IV form, the rest are oral agents)
78
What is the mechanism of action for bisphosphonates?
- They are analogues of pyrophosphate which allows for incorporation into bone
- Binds strongly to hydroxypatite undergoing remodelling
- Inhibits osteoclast activity at site
- Can also prevent osteoblast apoptosis
79
What are some commonly used Alendronate doses?
10mg OD
OR
70mg weekly
80
What are some commonly used Risedronate doses?
5mg OD
OR
35mg weekly
OR
150mg monthly
81
What is the dose for Zoledronic acid?
5mg/100mL administered IV once yearly
82
What are some dosing considerations for bisphosphonates?
- Extremely poor bioavailability (space administration from all drugs, food, drink, etc.)
- Remain upright for 30 minutes
83
What is the onset of effect for bisphosphonates?
- Weeks to observe bone changes
- Years to observe clinical benefit
84
What is the clinical benefit of bisphosphonate therapy?
- 20-30 fewer vertebral fractures/1000 people
- 10 fewer nonvertebral fractures/1000 people
- 3 fewer hip fractures/1000 people
85
What are some common side effects associated with bisphosphonate use?
- GI complaints (abdominal pain, dyspepsia, nausea, diarrhea)
- Headache
- Dizziness
- Musculoskeletal pain
- Transient decrease in blood calcium
86
What are some common side effects associated with zoledronic acid?
Infusion reaction: fever, myalgia, headache, flu-like symptoms, arthralgia
87
What are some serious side effects associated with bisphosphonate use?
- Osteonecrosis of the Jaw (especially concerning if dental surgery patient is on bisphosphonate therapy)
- Atypical sub-trochanteric fractures
- Severe musculoskeletal pain
- Acute renal injury
- Atrial fibrillation
- Esophagitis, reflex and ulcers
- Esophageal cancer
88
What is the concern for bisphosphonate use in pregnancy?
- Crosses the placenta and accumulates in fetal bones
- Animal models show harm (difficulties with delivery, bone abnormalities, hypocalcemia)
- Women who want to get pregnant should stop talking bisphosphonates for 1 year before concieving
89
What is the duration of therapy for bisphosphonates?
Needs to be highly individualized (most patients use them for 3 years, up to 6 years)
- Long bone half-lives, less benefit with long-term use (therefore drug holidays are reccomended)
90
What is the mechanism of action for Denosumab?
- Binds to RANKL (released by osteoblasts)
- RANKL is prevented from activating osteoclasts by Denosumab
91
Why is Denosumab used instead of bisphosphonates?
- Cannot adhere to dosing requirements of oral bisphosphonates
- Intolerance to oral bisphosphonates
- Severe renal impairment
92
What is the onset of effect for Denosumab?
- Markers of bone resorption markedly decreased within 3 days
- Maximal reduction within 1 month
93
What is the duration of therapy for Denosumab?
Indefinite treatment (benefits of denosumab rapidly lost after discontinuation)
94
How is Denosumab dosed?
60mg administered once every 6 months
Can be used down to CrCl of 30mL/min
95
What are some common side effects associated with denosumab?
- Very well tolerated (maybe rash/eczema or musculoskeletal pain)
96
What are some serious side effects associated with denosumab?
- Hypocalcemia
- Osteonecrosis of the jaw
- Atypical fractures
- Effect on the immune system
- Rebound fracture risk upon discontinuation (any gains are lost within 12-24 months)
97
What is the efficacy of Denosumab?
Observational data suggests similar fracture risk reduction vs. bisphosphonates
98
What is the mechanism of action for Raloxifene?
- Binds to estrogen receptors in bone and acts as an agonist (increases BMD)
- Acts asn estrogen antagonist in breast and uterine tissues (protective against cancer)
99
What is the onset of effect for Raloxifene?
Years to observe maximum BMD changes
100
How long is Raloxifene used for in osteoporosis treatment?
Life-long therapy
101
What are some common side effects associated with raloxifene use?
- Flushing
- Flu-like symptoms
- Leg cramps
- Peripheral edema
- Increase in TGs
102
What are some serious side effects associated with raloxifene?
Venous thromboembolism and stroke
103
What are some drug interactions associated with raloxifene use?
- No CYP enzyme interactions
- Bile acid sequestrants decrease absorption of raloxifene
- Raloxifene decrease absorption of levothyroxine
104
What is the efficacy of raloxifene?
Less BMD increases than Bisphosphonates and Denosumab
Beneficial in reducing risk for verterbral fractures (does not reduce risk for hip fractures)
Reduces risk of invasive breast cancer
105
What is the target population of hormone therapy in osteoporosis treatment?
Women with persistant menopausal symptoms and cannot tolerate bisphosphonates or denosumab
106
How long is hormone therapy for osteoporosis?
Maximum protection if used longer term and initiated shortly after menopause (not used indefinitely and needs to be reassessed every 1-12 months)
107
What are some safety concerns associated with hormone therapy?
- Increased endometrial/breast cancer risk
- Thromboembolism risk
- CHD risk increase
- Stroke risk
- Urinary incontinence
108
What is the efficacy of Teriparatide?
- More potent than bisphosphonates and denosumab (very expensive)
109
What is the mechanism of action for Teriparatide?
- Recombinant form of PTH (stimulates bone formation more than resorption)
110
How is Teriparatide dosed?
Most patients are on Teriparatide is used for only 2 years and it is dosed daily
111
What are some common side effects associated with Teriparatide?
- Nausea
- Dizziness
- Leg cramps
- Orthostatic hypotension/syncope
112
What are some serious side effects associated with Teriparatide use?
- Hypercalcemia (Ca2+ levels increase 10x, and drop to baseline after 4h)
- Hypercalciuria (risk of precipitating renal stones)
113
What are some contraindications for the use of Teriparatide?
- Pre-existing hypercalcemia
- Severe renal dysfunction
- HyperPTH
- History of bone cancers
- Pregnancy
114
What is done at the end of Teriparatide therapy to maintain the gains in BMD?
Patient is transitioned to a bisphosphonate or denosumab
115
What is the efficacy of Romosozumab?
More potent than bisphosphonates and denosumab
116
What is the mechanism of action for Romosozumab?
Humanized monoclonal antibody directed against sclerostin (targets regulation of osteoblasts and osteoclasts)
- Acts as an anabolic agent and anticatabolic
117
How long is Romosozumab used for?
- Treatment duration is 12 months
118
What are some common side effects associated with romosozumab use?
- Musculoskeletal/joint discomfort
- Headache
- Injection site pain/erythema
119
What is the efficacy of Romosozumab?
Similar to Teriparatide
120
Are combination therapies for osteoporosis useful?
While they do increase BMD, there are no additional fracture benefit
121
PHAR 255
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