Osteoporosis

Question 1

Parathyroid hormone

Answer 1

• Increases calcium absorption in the gut
• Increases bone resorption, leading to the release of calcium into the blood circulation
• Increases calcium resorption and phosphate excretion in the kidneys
• Increases hydroxylation of vitamin D precursors (aids calcium absorption in the gut)

Question 2

Vitamin D

Answer 2

Increases calcium and phosphate absorption in the gut,

promoting bone mineralisation

Question 3

Sex hormones

Answer 3

Oestrogen or androgen deficiency accelerates the remodelling rate causing loss of bone

Question 4

Growth hormones

Answer 4

Enhances collagen and non-collagen protein synthesis, aiding bone growth

Question 5

Glucocorticoids

Answer 5

Levels above the physiological norm reduce bone growth and lead to glucocorticoid-induced osteoporosis

Question 6

Thyroxine

Answer 6

Thyroid hormones stimulate both bone resorption and formation

Question 7

The World Health Organization defines osteoporosis as

Answer 7

“progressive systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture”

Question 8

Fragility fractures

Answer 8

Fragility fractures result from mechanical forces that would not ordinarily result in fracture, known as low level trauma.1 The WHO has quantified this as forces equivalent to a fall from a standing height or less. Typically, osteoporotic fractures occur in the vertebrae, wrist and hip. However, all fragility fractures in the elderly can be regarded as osteoporotic if secondary causes have been excluded. Elderly patients who are in long-term care are at high risk of osteoporotic fracture — at least 85% of women aged over 80 years who live in nursing homes are believed to have osteoporosis.

Question 9

Vertebrae

Answer 9

Vertebral fractures are a common manifestation of osteoporosis and, because they are usually asymptomatic, they can often go undetected.
Although hospital admissions due to vertebral fractures are rare, patients can experience back pain, and fracture related disability can have a significant impact on quality
of life. Patients who have vertebral fractures are at high
risk of having other fractures, including those to the hip,
and this should be taken into account when considering
treatment options.

Question 10

Hips

Answer 10

Hip fractures account for most of the health service
costs of osteoporosis. Approximately 50% of patients who
sustain a hip fracture will no longer be able to live independently and 20% die within 12 months of the
fracture. Hip fractures are usually caused by a fall, but can also occur spontaneously. For this reason, falls-related risk factors often overlap with risk factors for osteoporosis

Question 11

Risk factors for osteoporosis

Answer 11

Lifestyle factors
● High alcohol intake
● Smoking
● Poor nutrition
● Lack of exercise

Medical conditions
● Vitamin D deficiency
● Calcium deficiency
● Hyperthyroidism
● Abnormal thyroid function
● Cushing’s syndrome
● Rheumatoid arthritis
● Diabetes mellitus
● Haematological cancers
● Malabsorptive disorders
● Chronic liver disease
● Chronic renal disease
● Untreated hypogonadism
● Chronic obstructive pulmonary disease
● Immobility

Medicines
● Corticosteroids
● Aromatase inhibitors
● Tamoxifen
● Gonadotrophin-releasing hormone
● Proton pump inhibitors
● Phenytoin
● Carbamazepine
● Lithium
● Heparin
● Selective serotonin reuptake inhibitors
● Thiazolidinediones
● Methotrexate

Question 12

risk assessment tools

Answer 12

• FRAX

- QFracture

Question 13

FRAX

Answer 13

The WHO’s FRAX algorithm combines a patient’s
age, sex, height and weight along with seven clinical risk
factors (previous fracture, parent who has had a hip
fracture, current smoking, corticosteroid use, rheumatoid
arthritis, secondary osteoporosis and alcohol consumption of more than three units per day).
FRAX assessment can be performed for patients in whom BMD has not been measured, but adding a BMD result to the FRAX input data enhances the accuracy of the fracture prediction.

Question 14

QFracture

Answer 14

The QFracture algorithm can be used for individuals aged between 30 and 99 years and takes into account a number of risk factors that are not included in the FRAX assessment, such as ethnicity, history of falls, nursing or care home residence and secondary causes of osteoporosis, eg, diabetes.9 In contrast to FRAX, the QFracture algorithm cannot incorporate BMD values and the thresholds for treatment are less well defined.
Although these risk assessment tools can aid diagnosis and guide treatment, they use a formulaic approach to
assessing patients and cannot take into account individual confounders. This may lead to an overestimation or underestimation of actual fracture risk in some clinical situations

Question 15

Targeting risk assessment

Answer 15

The risk of fracture should be assessed in all women aged 65 years and older and all men aged 75 years and older. Women aged under 65 years and men aged under 75 years who have the following risk factors should also be assessed:
● Previous fragility fracture
● Current use or frequent use of oral or systemic
corticosteroids
● History of falls
● Family history of hip fracture
● Other causes of secondary osteoporosis
● Low body mass index (<18.5kg/m2)
● Smoking
● Alcohol intake of more than 14 units per week for
women and more than 21 units per week for men

Fracture risk should not be routinely assessed in
people under 50 years old, unless they have major risk factors (eg, current or frequent use of corticosteroids)

Question 16

Bone mineral density

Answer 16

BMD testing allows a clinician to diagnose high-risk patients with osteoporosis before a fracture occurs. F

Question 17

Bone mineral density scale

Answer 17

Normal >–1
A value of bone mineral density (BMD) within 1 standard deviation of the young adult reference mean

Low bone mass (osteopenia) –2.5
A value of BMD more than 1 standard deviation below the young adult reference mean but less than 2.5 standard deviations below this mean

Osteoporosis

Question 18

Bisphosphonates

Answer 18

Bisphosphonates are the most commonly prescribed
medicines for the prevention and treatment of osteoporosis. They bind to the surface of bones undergoing active remodelling and block the activity of osteoclasts.
Large phase III clinical trials have demonstrated that
bisphosphonate therapy significantly reduces vertebral
and hip fracture risk.

Oral - The use of oral bisphosphonates is frequently
associated with gastrointestinal side effects and there have been reports of serious upper gastrointestinal damage (oesophageal ulceration). Adhering to the administration requirements can minimise the risk of such adverse effects. Patients should be advised to:
● Take bisphosphonates on an empty stomach at least
30 minutes before breakfast (or other oral medicines)
● Swallow tablets whole with plenty of water while
sitting or standing
● Sit upright or stand for at least 30 minutes after taking a dose

There is a lack of safety data on the use of oral bisphosphonates for patients with renal impairment; therefore, alendronate and risedronate are not recommended for patients with an estimated glomerular
filtration rate (eGFR) of less than 35ml/min and 30ml/min, respectively. Gastrointestinal side effects and strict administration requirements are common reasons for non-adherence to bisphosphonate therapy. Thorough
counselling should be provided to patients who are being started on these medicines and regular monitoring to assess adherence is advised.

Question 19

Intravenous

Answer 19

Poor adherence to oral bisphosphonate therapy has led to an increase in the use of intravenous bisphosphonates. Zoledronic acid is the most potent bisphosphonate available and is administered as an intravenous infusion once a year. Data obtained from the HORIZON study found that, over three years, zoledronic acid reduced vertebral fractures by 70%, hip fractures by 41% and non-vertebral fractures by 25%.
Zoledronic acid should be avoided in patients with an
eGFR of less than 35ml/min. Patients should be adequately hydrated before the infusion and have their
renal function monitored. Hypocalcaemia can occur with
bisphosphonate treatment and is more common with
intravenous therapy. Existing hypocalcaemia should be
corrected before starting treatment. Furthermore, the risk
of osteonecrosis of the jaw (see Box 2, p96) is higher for
patients receiving intravenous bisphosphonate therapy.
Since zoledronic acid became available as a generic it is
now a more cost-effective option

Question 20

Drug holidays

Answer 20

There have been increasing concerns about the safety of the long-term use of bisphosphonates and questions have been raised as to what the optimum length of treatment should be. It is recommended that a treatment review should be performed after at least five years’ treatment with oral bisphosphonates and after three years of zoledronic acid treatment.
Long-term use of bisphosphonates can provide a residual
antiresorptive effect after treatment is stopped. This has
given rise to the concept of “drug holidays”, wherein
treatment can be stopped temporarily in patients who are
no longer at high risk of fracture.
However, the residual antiresorptive effect subsides over time and for patients who remain at high risk of fracture it may be prudent to continue with treatment. Therefore, the following groups of patients are not suitable for drug holidays:
● High-risk patients — ie, those who are aged 75
years and older, who have previously sustained a hip or vertebral fracture, or who are taking long-term oral corticosteroids (equivalent to 7.5mg or more of prednisolone daily)
● Patients who sustain one or more low trauma fractures during treatment (in whom poor adherence to treatment and causes of secondary osteoporosis have been excluded); in such cases treatment choice should be re-evaluated
● Patients whose total hip or femoral neck BMD T-scores are more severe than –2.5
If treatment is discontinued, fracture risk should be reassessed after two years if no new fracture occurs, or
after any new fracture, regardless of when this occurs.

Question 21

Denosumab

Answer 21

Denosumab is licensed for the prevention and treatment
of osteoporosis. It is a human monoclonal antibody that
targets the receptor activator of nuclear factor kappa B
ligand (RANKL), an important regulator of osteoclast
development and activity.
Clinical trials have shown that treatment with denosumab
increases BMD and decreases fragility fractures in patients with osteoporosis. However, there have been no
head-to-head trials comparing the efficacy of denosumab
in the reduction of fractures with that of other available
treatments.
NICE recommends denosumab for the secondary
prevention of osteoporotic fragility fractures in postmenopausal women who have an intolerance or
contraindication to oral bisphosphonates, or who are
unable to comply with the administration instructions.
Additional criteria are required for denosumab to be used
for primary prevention; it is not recommended in patients
with a T-score more severe than –3.8.
Denosumab is administered by subcutaneous injection
every six months and can be done so in primary care.
Calcium and vitamin D deficiency must be corrected before treatment begins. Patients who are at high risk of
hypocalcaemia (eg, those with renal impairment or who
are on dialysis) should have their calcium levels monitored during treatment. However, there is no dose adjustment of denosumab needed for patients with renal impairment.
Denosumab is more expensive than bisphosphonate
treatment, but substantially cheaper than teriparatide.

Question 22

Raloxifene

Answer 22

Raloxifene is a selective oestrogen receptor modulator. It
mimics the effect of oestrogen on the skeletal system
without causing the adverse effects that are commonly
associated with oestrogen use, but is contraindicated in
patients with a history of venous thromboembolism.
Selective oestrogen receptor modulators decrease the
accelerated rate of bone remodelling that is associated
with oestrogen deficiency in post-menopausal women,
thereby increasing bone mass. Although raloxifene has
been shown to reduce vertebral fractures, research has not demonstrated any efficacy in the prevention of hip or
other non-vertebral fractures

Question 23

Teriparatide

Answer 23

Teriparatide is a human recombinant parathyroid hormone that can increase osteoblast activity — stimulating bone formation — when given in intermittent doses of 20µg daily. Serum calcium, parathyroid hormone and 25-hydroxy-vitamin D levels must be checked before
treatment (hypercalcaemia and hyperparathyroidism are
among the contraindications to teriparatide therapy).
Teriparatide has been shown to reduce vertebral and
non-vertebral fractures in post-menopausal women.
There is no evidence to suggest it can reduce hip fractures specifically.
Teriparatide is expensive and only recommended for secondary prevention of fractures for patients with severe osteoporosis in whom other treatment options are unsuitable or have failed

Question 24

Strontium ranelate

Answer 24

The mechanism of action of strontium ranelate is not fully
understood. It is believed to reduce bone resorption and
maintain bone formation. Although there is sufficient
evidence to support the effectiveness of strontium
ranelate, particularly in vertebral fracture prevention,
post-marketing surveillance has raised concerns about its cardiovascular safety. This has been investigated by the
European Medicines Agency and final recommendations,
which were based on the analysis of pooled data from
randomised studies involving 7,500 post-menopausal
women, were released in February 2014. The use of
strontium ranelate has now been restricted to the
following groups:
● Individuals in whom other treatments are
contraindicated, ineffective or cannot be tolerated
● Post-menopausal woman with severe osteoporosis
Further EMA recommendations regarding the use of
strontium ranelate are:
● The drug must not be used for patients with an
established, current or past medical history of ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or uncontrolled hypertension
● Treatment should only be started by a clinician who
has experience in the treatment of osteoporosis
● Cardiovascular risk should be monitored every six to 12 months
● Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or uncontrolled hypertension
● All patients who are currently prescribed strontium
ranelate should be reviewed as necessary

Question 25

Supplementation

Answer 25

Adequate calcium and vitamin D intake is important for
maintaining skeletal health and this has been supported by several observational studies and randomised trial data.
For individuals who are deficient, calcium and vitamin D
supplementation alongside osteoporosis treatment is
recommended.
Low levels of vitamin D impair the intestinal absorption of calcium. This causes a compensatory rise in parathyroid hormone leading to excessive bone resorption.
The inactive form of vitamin D is synthesised when skin is exposed to sunlight and so a lack of sunshine can lead to vitamin D deficiency; populations at risk include elderly and housebound patients, and those who avoid sun
exposure for cultural or religious reasons. Vitamin D
deficiency can also result from inadequate dietary intake,
malabsorption of vitamin D and genetic abnormalities in
vitamin D metabolism.
Calcium and vitamin D supplementation is a safe and
inexpensive way to reduce fracture risk for people being
treated with bisphosphonates or denosumab and who have established vitamin D deficiency or are at a particularly high risk. Vitamin D levels are usually assessed by measuring serum concentrations of 25-hydroxy-vitamin D, the most abundant form of the hormone in the blood.
Vitamin D status is categorised according to 25-hydroxyvitamin D levels.
National Osteoporosis Society guidelines recommend
a loading regimen of approximately 300,000iu of vitamin
D (colecalciferol) divided over six to 10 weeks, followed
by maintenance therapy of 800–2,000iu daily for patients who require rapid correction of levels. Where the
correction of vitamin D deficiency is less urgent and when co-prescribing vitamin D supplements with an oral
antiresorptive medicine, maintenance therapy may be
started without the use of loading doses

Question 26

Complications of therapy

Answer 26

Atypical femoral fracture
- There is an increased risk of atypical femoral fracture (AFF) occurring with bisphosphonate use, mainly in patients receiving long-term treatment.
Patients who develop prodromal pain of the thigh, groin or hip during treatment with these medicines must be advised to report the symptoms immediately. Patients who develop AFFs should have their bisphosphonate
treatment discontinued and alternative treatment options should be considered. There have been case reports of AFF occurring in patients taking denosumab, but it remains to be determined if this has been caused by denosumab treatment or other factors.

Osteonecrosis of the jaw

• Osteonecrosis of the jaw occurs rarely in patients receiving bisphosphonate or denosumab therapy for osteoporosis. Good oral hygiene should be maintained during treatment and routine dental check-ups should be
  advised. Bisphosphonate or denosumab therapy should not be regarded as a contraindication to necessary dental treatment

Question 27

Primary prevention

Answer 27

The National Institute for Health and Care Excellence recommends that alendronate should be used first line for the primary prevention of osteoporosis for post-menopausal women who have a T-score, measured by dual-energy X-ray absorptiometry (DXA) scanning, of 2.5 standard deviations or more below the young adult reference mean and meet the following criteria:

● Aged under 64 years with an independent clinical risk factor (IRF) and at least one additional indicator of low bone mineral density (BMD)
● Aged 65–69 years with an IRF
● Aged 70 years or older with an IRF or an indicator of low BMD
● Aged 75 years or older with two or more IRFs or indicators of low BMD (DXA scanning is not required)
Risedronate, etidronate and strontium ranelate are recommended second and third line if patients meet certain criteria involving Tscores and numbers of IRFs and indicators of low BMD. Raloxifene and teriparatide are not recommended for the primary prevention of osteoporosis.
In contrast, the National Osteoporosis Guideline Group
guidelines are less prescriptive. Generic bisphosphonates
(alendronate and risedronate) are recommended first line for men and women aged 50 years or older who have been deemed suitable for treatment according to the FRAX algorithm. For individuals who are intolerant to generic bisphosphonates or in whom these medicines are contraindicated, alternative bisphosphonates, denosumab, raloxifene and strontium ranelate can be considered as treatment options. Teriparatide is recommended only for patients
who are at very high risk of fractures, particularly vertebral fractures.
Despite the increase in bone mass demonstrated by use of hormone replacement therapy, the side effects associated with its use make it no longer suitable for the prevention and treatment of osteoporosis.

Question 28

Secondary prevention

Answer 28

Alendronate is recommended first line by NICE for the secondary prevention of fragility fractures in post-menopausal women who have a confirmed diagnosis of osteoporosis (T-score –2.5). BMD testing is not required for women over the age of 75 years for treatment to be initiated.
Second- and third-line treatments (risedronate, etidronate,
strontium ranelate and raloxifene) are recommended on the basis of meeting additional criteria. Teriparatide is recommended as an alternative for individuals in whom other treatments are contraindicated, ineffective or poorly tolerated. Specific criteria have been outlined for the subset of patients who can be offered teriparatide. Again, NOGG guidelines recommend using the FRAX algorithm to identify patients who should be offered treatment for
secondary prevention. Oral bisphosphonates are recommended first line and alternative treatment options should only be considered if bisphosphonates are unsuitable.

Question 29

Regarding the structure and function of the human skeleton:
a) The bones serve as a reservoir for growth factors
and cytokines
b) The skeleton is a dynamic organ that is continually regenerating
c) The outer part of all skeletal structures is made up of trabecular bone
d) Cortical bone is composed of a porous spongelike structure
e) Each skeletal site is composed of different ratios of cortical and trabecular bone

Answer 29

a) T
b) T
c) F
d) F
e) T

Question 30

Concerning the remodelling of bone:

a) Loss of bone, the hallmark of osteoporosis, can be caused by an imbalance between bone formation and bone resorption
b) Resorption of old bone is performed by osteoblasts
c) Apoptosis of osteocytes produces signals that initiate remodelling of bone
d) Parathyroid hormone decreases bone resorption
e) Oestrogen deficiency reduces the rate of bone remodelling

Answer 30

a) T
b) F
c) T
d) F
e) F

Question 31

The following factors can increase a person’s risk of developing osteoporosis:

a) Smoking
b) Poor nutrition
c) Hypercalcaemia
d) Corticosteroid use
e) Rheumatoid arthritis

Answer 31

a) T
b) T
c) F
d) T
e) T

Question 32

Osteoporotic fragility fractures:

a) Cost the NHS £2.2bn in 2013
b) Are associated with a significant risk of mortality and morbidity
c) Can result from low level trauma that would not ordinarily result in fracture
d) Typically occur in the vertebrae, wrist and hip
e) To the vertebrae account for most of the health costs of osteoporosis

Answer 32

a) F
b) T
c) F
d) T
e) F

Question 33

Regarding the assessment of fracture risk:

a) The FRAX and QFracture assessment tools calculate the 20-year probability of hip, wrist or vertebrae fracture
b) Incorporating a bone mineral density result into a FRAX assessment increases the accuracy of the prediction
c) QFracture takes into account more risk factors than the FRAX assessment
d) A dual-energy X-ray absorptiometry scan quantifies bone mineral density
e) A T-score value of 2 standard deviations below the young adult reference mean is indicative of severe osteoporosis

Answer 33

a) F
b) T
c) T
d) T
e) F

Question 34

According to the National Institute for Health and Care Excellence, second- or third-line treatment options for the primary prevention of osteoporosis can include:

a) Alendronate
b) Risedronate
c) Strontium ranelate
d) Teriparatide
e) Raloxifene

Answer 34

a) F
b) T
c) T
d) F
e) F

Question 35

Bisphosphonates:

a) Are the most commonly prescribed medicines for osteoporosis
b) Block the activity of osteocytes
c) Must be taken after food
d) Are frequently associated with gastrointestinal side effects
e) Can provide a residual antiresorptive effect for some time after long-term treatment is stopped

Answer 35

a) T
b) F
c) F
d) T
e) T

Question 36

A “drug holiday” from bisphosphonate therapy would not be recommended for a patient who:

a) Has been taking alendronate for two years
b) Has been receiving zolendronic acid treatment for four years and is at low risk of fracture
c) Is 80 years old and has a history of hip fracture
d) Has sustained a fragility fracture during treatment
e) Has a bone mineral density T-score of –4

Answer 36

a) T
b) F
c) T
d) T
e) T

Question 37

Regarding the medicines used in the prevention and treatment of osteoporosis:

a) Denosumab affects the receptor activator of nuclear factor kappa B ligand (RANKL)
b) Denosumab is contraindicated in patients with renal impairment
c) Raloxifene blocks the effect of oestrogen on the skeletal system
d) Teriparatide is reserved for patients who are at very high risk of fractures
e) Strontium ranelate is not suitable for patients who have a history of stroke

Answer 37

a) T
b) F
c) F
d) T
e) T

Question 38

Concerning vitamin D:
a) Supplementation is recommended for all patients
receiving treatment for osteoporosis
b) Low levels impair the intestinal absorption of calcium
c) Deficiencies can result from a lack of exposure to sunshine
d) 25-hydroxy-vitamin D levels over 60ng/ml are considered optimum
e) For patients who require rapid correction of levels, the National Osteoporosis Society recommend a loading regimen of 8,000iu of colecalciferol taken over six to 10 weeks

Answer 38

a) F
b) T
c) T
d) F
e) F

Question 39

Preventing fragility fractures - treatment

Answer 39

• Bisphosphonates: Alendronic acid (1st line), Risendronate Sodium (1st line) or ibandronic acid only if:
  
  • Patient is eligible and 10 year risk is atleast 1%
• IV bisphosphonates: Ibrandronic acid or Zoledronic acid only if:
  
  • Patient has 10 year risk of atleast 10% or 1% if patient cannot take PO

Question 40

Alendronic acid dose for preventing fragility fractures

Answer 40

10mg OD

Question 41

Risendronate Sodium dose for preventing fragility fractures

Answer 41

5mg OD

Question 42

ibandronic acid dose for preventing fragility fractures

Answer 42

150mg monthly

Question 43

Zoledronic acid dose for preventing fragility fractures

Answer 43

5mg yearly

Question 44

Alternative primary prevention for post menopause

Answer 44

• Denosumab 60mg every 6 months SC

- Do not give raloxifene for primary prevention

Question 45

What can be given for sereve osteoporosis in post menopausal women

Answer 45

• Teriparatide. Limited to 24 months treatment 20mg OD

Question 46

When should treat with alendronic acid or Risendronate Sodium be reviewed

Answer 46

Every 5 years

Question 47

When should treat Zoledronic acid be reviewed

Answer 47

Every 3 years

Question 48

Are bisphosphonates safe to use in pregnancy

Answer 48

No