Osteoporosis Flashcards
Parathyroid hormone
- 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)
Vitamin D
Increases calcium and phosphate absorption in the gut,
promoting bone mineralisation
Sex hormones
Oestrogen or androgen deficiency accelerates the remodelling rate causing loss of bone
Growth hormones
Enhances collagen and non-collagen protein synthesis, aiding bone growth
Glucocorticoids
Levels above the physiological norm reduce bone growth and lead to glucocorticoid-induced osteoporosis
Thyroxine
Thyroid hormones stimulate both bone resorption and formation
The World Health Organization defines osteoporosis as
“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”
Fragility fractures
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.
Vertebrae
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.
Hips
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
Risk factors for osteoporosis
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
risk assessment tools
- FRAX
- QFracture
FRAX
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.
QFracture
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
Targeting risk assessment
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)
Bone mineral density
BMD testing allows a clinician to diagnose high-risk patients with osteoporosis before a fracture occurs. F
Bone mineral density scale
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
Bisphosphonates
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.
Intravenous
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
Drug holidays
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.
Denosumab
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.
Raloxifene
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
Teriparatide
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
Strontium ranelate
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
