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Bone metabolism > Osteoporosis > Flashcards

Osteoporosis Flashcards

1
Q

Osteoporosis definition
(WHO) using T-score

A

The World Health Organization (WHO) definition of osteoporosis is a bone mineral density (BMD) T-score at the femoral neck of 2.5 standard deviations (SD) or more below the average value in young women.

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2
Q

Severe osteoporosis definition

A

Severe osteoporosis (or established osteoporosis) is defined as having a BMD of
2.5 SD below that of a young female adult, with the presence of one or more fragility
fractures.

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3
Q

NOGG recommends the following investigations to exclude diseases that may mimic osteoporosis and to identify causes of secondary osteoporosis:

A

Full blood count, erythrocyte sedimentation rate, c-reactive protein, serum calcium, albumin, creatinine, phosphate, alkaline phosphatase, liver transaminases and thyroid function tests.

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4
Q

Investigations to identify causes of secondary osteoporosis:

A
  • Lateral spine x-ray : to look for vertebral fractures .
  • Serum immunoglobulins and electrophoresis, and urinary Bence-Jones protein: to identify myeloma .
  • Endomysial or tissue transglutaminase antibodies: to identify coeliac disease .
  • Parathyroid hormone: If abnormal calcium levels, to exclude primary hyperparathyroidism.
  • Serum testosterone, sex hormone binding globulin, follicle stimulating hormone and lutenising hormone (in men): to assess hypogonadism.
  • Serum prolactin: elevated in prolactinoma or in patients taking some anti-psychotics.
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5
Q

BTM

A

Bone turnover markers, eg
- anabolic: osteocalcin, bone ALP, PINP, …
- catabolic: CTX, NTX, …

see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549920/

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6
Q

CTX

A

C-terminal telopeptides of type I collagen.

It is considered the reference marker for resorption.

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7
Q

NTX

A

N-terminal telopeptides of type I collagen

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8
Q

DPD

A

Deoxy-pyridinoline
Deoxypyridinoline, also called D-Pyrilinks, Pyrilinks-D, or deoxyPYD, is one of two pyridinium cross-links that provide structural stiffness to type I collagen found in bones.

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9
Q

PYD

A

Pyridinoline

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10
Q

PINP

A

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis.

[type 1]

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11
Q

PICP

A

C-terminal propeptide of type 1 collagen

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12
Q

Qualitative definition of osteoporosis

A

“Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture”
Consensus Development Conference, 2001

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13
Q

WHO diagnostic criteria for osteoporosis

A
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14
Q

FLS

A

Fracture Liaison Services

Fracture Liaison Service Database (FLS-DB)

FLS provide secondary prevention for fragility fractures.

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15
Q

Fragility fracture

A

a fracture following a fall from standing height or less

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16
Q

BIGoS

A

Bone Interest Group of Scotland

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17
Q

BMD-dependent factors affecting fracture risk

A

*Female sex
*Premature menopause
*Amenorrhoea
*Hypogonadism
*Ethnic origin
*Excessive alcohol
*Immobilisation
*Low dietary calcium intake
*Vitamin D deficiency

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18
Q

BMD-independent factors affecting fracture risk

A

*Age
*Prior fragility fracture
*Glucocorticoids
*Family history of fracture
*Poor visual acuity
*Low body mass index
*Neuromuscular disorders
*Smoking

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19
Q

Fracture risk assessment

A

Fracture risk assessment
NICE recommends a targeted fracture risk assessment for:
* all women aged 65 and over
* all men aged 75 and over
* women or men under 65 if they have any of the following risk factors:
* previous fragility fracture
* current or frequent recent use of oral or systemic glucocorticoids
* a history of falls
* family history of hip fracture
* BMI <18.5kg/m2
* smoking
* alcohol intake exceeding 14 units per week.

NICE does not recommend using assessment tools routinely in patients under 50, unless there are major risk factors for osteoporosis and fragility fractures, for example:
- current or frequent recent use of oral or systemic glucocorticoids,
- untreated premature menopause or
- previous fragility fracture.

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20
Q

Aromatase inhibitors

A

Aromatase inhibitors (such as anastrozole, exemestane (Aromasin) and letrozole) reduce the amount of oestrogen made in the body, which can reduce bone density and cause fractures.

NICE recommends that patients should have a DEXA scan prior to starting treatment with aromatase inhibitors.

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21
Q

Risk factors for osteoporosis and fragility fractures -
non-modifiable

A
  • Previous fragility fracture
  • Parental history of osteoporosis
  • Family (parental) history of hip fractures
  • Age: the risk of osteoporosis rises with increasing age and steeply in women over 65 and men over 75
  • Gender (4 times more likely in women than men)
  • Ethnicity (Caucasian and Asian women are at highest risk)
  • Premature/early menopause (<40 years, according to NICE, <45 according to NOGG)
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22
Q

Risk factors for osteoporosis and fragility fractures -
modifiable

A
  • Low BMI (<20 kg/m2 according to SIGN; NICE says <18.5 kg/m2 )
  • Smoking
  • Alcohol > 3 units per day. (NICE says over weekly quantities of 14 units for men and women)
  • Low BMD
  • diet low in calcium and vitamin D
  • Lifestyle (an inactive lifestyle or extended bed rest)
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23
Q

Risk factors for osteoporosis and fragility fractures -
chronic disease

A
  • Diabetes mellitus
  • Inflammatory connective tissue diseases, for example rheumatoid arthritis, systemic lupus eryhematosus (SLE), ankylosing spondylitis
  • Inflammatory or malabsorptive bowel disease, e.g. Crohn’s disease or coeliac disease
  • Primary and secondary hyperparathyroidism, thyrotoxicosis, Cushing’s disease and other endocrine diseases - hypogonadism, primary ovarian failure, adrenal gland hyperplasia
  • Chronic liver disease
  • Neurological diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and epilepsy.
  • Moderate to severe chronic kidney disease (CKD): stage 3-5
  • Asthma
  • Conditions that result in prolonged immobility
  • HIV
  • Bone cancer
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24
Q

Risk factors for osteoporosis and fragility fractures -
medication

A
  • Oral glucocorticoids (long-term systemic use of corticosteroids)
  • Proton pump inhibitors (PPIs)
  • Long term anti-depressants usage, especially selective serotonin reuptake inhibitors (SSRls)
  • Thiazolidinedione drugs (TZDs ) -pioglitazone
  • Anti-epileptic drugs, especially valproate, carbamazepine , primidone and phenytoin
  • The long acting contraception medroxyprogesterone acetate (Depo-Provera@). Use for 2 years or more can
    reduce bone density, but this and overall fracture risk is reversed rapidly on stopping treatment
  • GnRH analogues for men undergoing prostate cancer treatment. Interestingly there are no studies identifying increased fracture risk in women undergoing GnRH therapy, possibly because they only tend to take the drugs for a relatively short time, for example to shrink fibroids
  • Aromatase inhibitors for treatment of breast cancer

Examples of the GnRH: Decapeptyl (triptorelin acetate), Zoladex (gosarelin acetate) and Prostap (leuprorelin acetate).

25
Q

TODO

A
  • learn chronic diseases that are risk factors for OP
  • learn medications that are risk factors for OP
26
Q

Colecalciferol with calcium carbonate (BNF)

A

Accrete D3® contains calcium carbonate 1.5 g (calcium 600 mg or Ca2+ 15 mmol), colecalciferol 10 micrograms (400 units);

Adcal-D3® tablets contain calcium carbonate 1.5 g (calcium 600 mg or Ca2+ 15 mmol), colecalciferol 10 micrograms (400 units);

Cacit® D3 contains calcium carbonate 1.25 g (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 11 micrograms (440 units)/sachet;

Calceos® contains calcium carbonate 1.25 g (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 10 micrograms (400 units);

Calcichew-D3® tablets contain calcium carbonate 1.25 g (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 5 micrograms (200 units);

Calcichew-D3® Forte tablets contain calcium carbonate 1.25 g (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 10 micrograms (400 units);

Calcichew-D3® 500 mg/400 unit caplets contain calcium carbonate (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 10 micrograms (400 units);

Kalcipos-D® contains calcium carbonate (calcium 500 mg or Ca2+ 12.5 mmol), colecalciferol 20 micrograms (800 units);

Natecal D3® contains calcium carbonate 1.5 g (calcium 600 mg or Ca2+ 15 mmol), colecalciferol 10 micrograms (400 units).

27
Q

Diet - calcium intake

https://theros.org.uk/information-and-support/bone-health/nutrition-for-bones/calcium/calcium-rich-food-chooser/

A

Recommended daily dose for adults aged 19 to 64 and over: 700 mg.

Examples of calcium content (from high to low):
1. Malted milk drink
2. Cheese
3. Tofu
4. Whitebait
5. Wholemeal bread

Whitebait is a collective term for the immature fry of fish, typically between 25 and 50 millimetres long.

Taking high doses of calcium (more than 1,500mg a day) could lead to stomach pain and diarrhoea.

28
Q

Calcium calculator

A

https://webapps.igc.ed.ac.uk/world/research/rheumatological/calcium-calculator/

29
Q

Instances when the DEXA may give false results

A
  • crush fractures,
  • kyphosis,
  • significant degenerative disease or
  • aortic calcification.
30
Q

DEXA cannot distinguish between osteoporosis and several other metabolic bone disorders such as:

A
  • various types of osteomalacia,
  • osteitis fibrosa,
  • uremic osteodystrophy,
  • hypophosphatasia,
  • Paget’s disease of bone
  • …
31
Q

NOGG recommends the following investigations to exclude diseases
that may mimic osteoporosis and to identify causes of secondary
osteoporosis:

A
  • Full blood count,
  • erythrocyte sedimentation rate,
  • c-reactive protein,
  • serum calcium,
  • albumin,
  • creatinine,
  • phosphate,
  • alkaline phosphatase,
  • liver transaminases and
  • thyroid function tests.
32
Q

Additional investigations to identify causes of secondary osteoporosis

A
  • Lateral spine x-ray - To look for vertebral fractures
  • Serum immunoglobulins and electrophoresis and urinary Bence-Jones protein - Identify myeloma
  • Endomysial or tissue transglutaminase antibodies - Identify coeliac disease
  • Parathyroid hormone - If abnormal calcium levels, to exclude primary hyperparathyroidism
  • Serum testosterone, sex hormone binding globulin, follicle stimulating hormone and lutenising hormone (in men) - To assess hypogonadism
  • Serum prolactin - Elevated in prolactinoma or in patients taking
    some anti-psychotics
33
Q

Bisphosphonates - Contraindications

A
  1. History of hypersensitivity to the bisphosphonate
  2. Hypocalcemia
  3. Chronic kidney disease with a glomerular filtration rate of less than 30 to 35 mL/min
  4. Avoid oral bisphosphonates in patients with esophageal disorders such as achalasia, esophageal stricture, esophageal varices, Barrett’s esophagus, inability to stand or sit upright for at least 30 minutes, history of bariatric surgery (Roux-en-Y gastric bypass).
  5. History of atypical femur fracture secondary to bisphosphonates
  6. History of osteonecrosis of the jaw secondary to bisphosphonates.
  7. (relative) during pregnancy and lactation period.
34
Q

Diagnosis and treatment of osteoporosis according to FRAX 10-year fracture score

A

The National Osteoporosis Foundation recommends treating patients with FRAX 10-year risk scores of ‘greater than or equal to 3 percent’ for hip fracture or ‘greater than or equal to 20 percent’ for a major osteoporotic fracture to reduce fracture risk.

The Bone Health and Osteoporosis Foundation (BHOF)’s treatment guidelines state that a patient should be diagnosed with osteoporosis if their 10-year risk of hip fracture is 3% or higher or if they have a 20% chance or greater of experiencing a major osteoporotic fracture, as calculated by FRAX.

35
Q

What Does Your FRAX Score Mean?

A

What should your FRAX score be?

A normal FRAX score is when the chance of getting a fracture in the next decade is less than 10%Trusted Source.
What is a moderate risk FRAX score?

Moderate risk for fractures is defined as between 10% and 20% chance of getting a fracture in the next decade.
What FRAX score indicates osteoporosis?

The Bone Health and Osteoporosis Foundation (BHOF)’s treatment guidelines state that a patient should be diagnosed with osteoporosis if their 10-year risk of hip fracture is 3% or higher or if they have a 20% chance or greater of experiencing a major osteoporotic fracture, as calculated by FRAX.

https://www.healthline.com/health/frax-score#fa-qs

36
Q

Zoledronate (zoledronic acid)

A

Brand name Aclasta.

37
Q

Bisphosphonates - Relative potency

A

Etidronate 1 [not in the UK]
Tiludronate 10 [not in the UK]
Pamidronate 100
Alendronate 100-500
Ibandronate 500-1000
Risedronate 1000
Zoledronate 5000

38
Q

Aetiology of stress fractures

A
  • Fatigue reaction stress fractures (overuse fractures): abnormal stresses on normal bone.
  • Insufficiency reaction stress fractures : normal stresses on abnormal bone (most often in osteoporosis, but also in many other diseases).

Fatigue fractures occur in normal bone that has been overused (e.g. in athletes and military personnel), whereas insufficiency fractures develop in fragile bone that is repeatedly subjected to low levels of stress during everyday physical activity.

https://www.ncbi.nlm.nih.gov/books/NBK554538/

39
Q

Aetiology of insufficiency fractures

A
  • disrupted bone mineral homoeostasis: hyperparathyroidism, diabetes mellitus, osteomalacia
  • bone remodelling: Paget disease, osteopetrosis
  • collagen formation: Marfan syndrome, fibrous dysplasia
  • medications: glucocorticoids, chemotherapy
  • radiation therapy​
40
Q

2L4 Bisphosphonate Toxicity

A

https://www.ncbi.nlm.nih.gov/books/NBK562331/

41
Q

ONJ

A

Osteonecrosis of the jaw
The overall incidence of osteonecrosis of the jaw was 2% compared to that for patients taking oral bisphosphonates for osteoporosis, where it ranges from about 1 in 10,000 to 1 in 100,000 patient-years.

https://www.ncbi.nlm.nih.gov/books/NBK562331/

42
Q

AFF

A

Atypical femur fractures
Atypical fractures are seen with the long-term use of bisphosphonates (median use of 7 years). The absolute risk of such fractures ranges between 3.2 to 50 cases per 100000 patient-years.[7]

https://www.ncbi.nlm.nih.gov/books/NBK562331/

43
Q

Licensed treatments for OP (UK)

A

Antiresorptive:
* Bisphosphonates
- Alendronate (Fosamax)
- Risedronate (Actonel)
- Ibandronate (Bonviva)
- Zoledronate (Aclasta in the E.U; Zometa and Reclast in the U.S.)
* denosumab (Prolia)
* HRT
* raloxifene (as per SIGN)

Selective oestrogen receptor
modulators (SERMs):
* raloxifene (Evista)

Anabolic:
* teriparatide (rhPTH(1-34)) (Forteo, Movymia, Terrosa, Teriparatide Teva)
* romosozumab (Evenity)
* abaloparatide (Eladynos, Tymlos ) - in development
July 2024

Adjunctive
* Calcium and vitamin D

Dual role as antiresorptive and some bone-forming activity
* strontium ranelate

44
Q

Aim to reduce fracture risk

A

Vertebral fractures ~50%
* 70% zoledronate, denosumab, PTH (teriparatide), romosozumab.

Non-vertebral fractures
* Hip up to 40%
* Peripheral ~20%

45
Q

Romosozumab

A

Increases new bone formation and decreases bone resorption.
Monoclonal antibody to sclerostin
Monthly subcutaneous injection for 12 months
Vertebral fracture risk reduction ~73%
Superior to alendronic acid in head-to-head study
SE:
* Increased risk of cardiovascular death, stroke and myocardial infarction vs. alendronic acid.
* Currently contraindicated in patients with history of myocardial infarction or stroke.

46
Q

Bisphosphonates - Adverse Effects

A

Common
Gastro-intestinal
Acute phase response

Uncommon
Iritis
Atrial fibrillation

Very uncommon (bisphosphonates and denosumab)
Osteonecrosis of the jaw
Atypical femoral fractures

47
Q
A
48
Q

Vertebral Fracture grades

A

Vertebral Fracture Assessment Using a Semiquantitative Technique, by Genant et al., was published and evaluatedosteoporotic fractures; this has wide acceptance and utilization. The scale looks at the shape of the vertebrae and measures the loss of height (LOH). It starts at grade 0 for normal vertebrae, grade 1 for mild fracture of 20 to 25% LOH, grade 2 for moderate fracture 25 to 40% LOH, grade 3 for severe fracture showing LOH at greater than 40%

49
Q

Vertebral Fracture grades

A

Vertebral Fracture Assessment Using a Semiquantitative Technique, by Genant et al., was published and evaluatedosteoporotic fractures; this has wide acceptance and utilization. The scale looks at the shape of the vertebrae and measures the loss of height (LOH). It starts at grade 0 for normal vertebrae, grade 1 for mild fracture of 20 to 25% LOH, grade 2 for moderate fracture 25 to 40% LOH, grade 3 for severe fracture showing LOH at greater than 40%

50
Q

RANK

A

RANK (receptor activator of nuclear factor-kappa-B). It is found on osteoclast precursors. RANK is a membrane-bound, TNF-like receptor that recognizes RANKL through direct cell-to-cell interaction with osteoblasts.

51
Q

What is the full name of NF-kappa-B?

A

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) comprises a family of five transcription factors.

52
Q

Denosumab

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099366/

A

= monoclonal antibody against RANKL [which is found on osteoblasts].

Indications (SIGN): non-severe OP, if not for bisphosphonates (both oral and IV). Treat for 5 years, then re-Ax, then either continue to 10 years or transition to bishosphonates. See BNF for other indications, eg bone loss due to steroids.

Brand name: Prolia.

Administration: once every 6 months (+/- 1 month) as a 60-mg subcutaneous injection. During treatment, calcium and vitamin D supplementation is important.

CI: hypocalcaemia, intolerance to fructose/sorbitol, pregnancy, breast-feeding.

SE: see PIL and BNF

Caution: When used for Osteoporosis in postmenopausal women: Rebound increase in bone turnover on discontinuation (increased risk of fracture).

53
Q

OPG

A

Osteoprotegerin = osteoclastogenesis inhibitor factor = a decoy receptor for RANKL, which can effectively inhibit RANKL-RANK interaction and mediate bone remodeling.

It is increased by estrogens.

54
Q

RANKL

A

= receptor activator of nuclear factor kappa beta (NFkB ligand). It is also commonly referred to as osteoprotegerin ligand (OPGL) or osteoclast differentiation factor (ODF) or TNF related activation-induced cytokine (TRANCE).

RANKL is formed by osteoblasts and some other cells like activated T cells, in both cell associated and secreted forms, the latter derived by proteolytic action. It is a member of the tumour necrosis factor (TNF) superfamily.

55
Q

OAF

A

Osteoclast activating factor = interleukin 1 beta (IL-1B)

56
Q
A
57
Q

Activators of osteoblasts precursors

A

IGF, PTH, vit D

58
Q

Bisphosphonates - MOA

A
  • bind to hydroxyapetite
  • get ingested by osteoclasts
  • induce osteoclasts apoptosis

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