Rheumatology

Bisphosphonates in the treatment of osteoporosis

BMJ 22 May 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important
new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham
and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic for this series, please email us at practice@bmj.com.

A 74 year old woman is admitted to hospital with a

subtrochanteric hip fracture after a fall in her home. The T score for the bone mineral density (BMD) in her femoral neck is −3.2.
She had a wrist fracture seven years ago but is otherwise healthy.
Her 10 year absolute risk of any major osteoporotic fracture is 23%.


The patient is treated surgically with internal
fixation of the fracture. She is advised that she has a high risk of having further fractures, and the benefits and risks of possible treatment options to reduce this risk are discussed using adecision aid (http://musculoskeletal.cochrane.org/decision-aids).
It is agreed that she will take alendronate, 70 mg once weekly for five years.

What are bisphosphonates?

Bisphosphonates are analogues of inorganic pyrophosphate.
They inhibit bone resorption by inducing apoptosis of
osteoclasts,1 thus preventing age related bone loss and deterioration of bone microarchitecture. Bisphosphonates that contain nitrogen (such as alendronate, risedronate, ibandronate,
and zoledronic acid) have the most potent antiresorptive properties and are the most commonly used drugs in the treatment of osteoporosis.

The bisphosphonate etidronate does not contain nitrogen, and although it is approved for treatment
of postmenopausal osteoporosis, the evidence base is weaker and it is rarely prescribed nowadays.
How well do bisphosphonates work?
Large phase III randomised controlled trials in postmenopausal women with osteoporosis have shown significant reduction in vertebral fractures after three years of treatment with

Alendronate, risedronate, ibandronate, and zoledronic acid, and in non-vertebral fractures and hip fractures with alendronate, risedronate, and zoledronic acid. In the Fracture Intervention Trial, the incidence of vertebral fracture in women treated for three years with alendronate 5 mg daily for 24 months followed by 10 mg daily for 12 months was 8%, compared with 15% in the placebo group (P=0.001); corresponding figures for
hip fracture were 1.1% and 2.1% (P=0.05).

In women treated for three years with zoledronic acid, 5 mg once yearly, the incidence of vertebral fractures was 3.3% compared with 10.9% in the placebo group (P<0.001) and of hip fractures was 1.4% compared with 2.5% (P<0.001).6 Retrospective subgroup analyses have also shown a reduction in non-vertebral fracture
with ibandronate.


The trials in men at increased risk of fracture
and in individuals taking glucocorticoids were not designed to show fracture reduction, but alendronate, risedronate, and
zoledronic acid have similar effects on BMD to those observed in postmenopausal women.
Calcium and vitamin D supplements were given in all the trials.

Direct comparison of the efficacy of different bisphosphonates in reducing fractures is not possible, as trial populations and designs in pivotal clinical trials have differed and head to head studies with fracture as the primary endpoint have not been performed. Comparison between bisphosphonates of the number
needed to treat to prevent a fracture is unreliable because of the dependence of this estimate on the underlying risk of the trial population, which differs between studies and is an important
determinant of absolute risk reduction with treatment.

However, on the basis of clinical trial data for alendronate and zoledronic acid, the estimated numbers needed to treat for postmenopausal
women with a vertebral fracture and/or a BMD T score ≤−2.5 were 90 for hip fracture, 25 for any non-vertebral fracture (including hip), and 14 for vertebral fracture over three years.

Both the National Institute for Health and Clinical Excellence (NICE) and the UK National Osteoporosis Guideline Group recommend alendronate as the first line treatment option for primary or secondary prevention of fracture in postmenopausal women. NICE recommends etidronate or risedronate as second line options in women who cannot take or tolerate
alendronate but has not conducted an appraisal of ibandronate or zoledronate.

The National Osteoporosis Guideline Group

considers risedronate, ibandronate, and zoledronic acid to be second line agents.
How safe are bisphosphonates?
Gastrointestinal adverse effects (including oesophagitis, gastritis,dyspepsia, oesophageal reflux, nausea, abdominal pain, and
diarrhoea) may occur in patients taking oral bisphosphonates.


Although in most clinical trials these were not significantly more common in treated patients than in placebo patients, post-marketing studies indicate that some increase in risk exists,
particularly if the dosing instructions are not followed correctly (see box on tips for patients).13 Musculoskeletal pain, rash, and headache occur with a frequency of ≥1/100, <1/10) and ocular
inflammation (uveitis and iritis) rarely occurs (≥1/10 000,<1/1000).

Osteonecrosis of the jaw has been reported in patients taking bisphosphonates, mainly in patients with cancer who are receiving higher doses than those used for osteoporosis. A causal association with bisphosphonates has not been shown and the
condition is very rare in patients with osteoporosis (incidence estimated at between 1/10 000 and 1/100 000 patient years).

Atypical subtrochanteric and diaphyseal femoral fractures have also been described in patients treated with bisphosphonates for osteoporosis. They occur after minimal or no trauma, are often associated with prodromal pain, heal poorly, and are
bilateral in nearly half of cases. They are rare, accounting for about 1% of all hip and femoral fractures; the estimated incidence being 5/10 000 per year of bisphosphonate use.

Radiologically, atypical subtrochanteric and diaphyseal femoral fractures present as short oblique or transverse fractures, sometimes progressing from a stress fracture in the lateral cortex.
Concerns about a possible increased risk of atrial fibrillation and oesophageal cancer in patients taking bisphosphonates have been raised, but the evidence is inconclusive.

What are the precautions?

Oral bisphosphonates are very poorly absorbed (usually <1% absorption) and may cause oesophageal irritation if in prolonged
contact with the oesophageal mucosa. Do not prescribe bisphosphonates if any of the following conditions apply:

Delayed oesophageal emptying owing to oesophageal

abnormalities such as achalasia or stricture (caution applies to oral bisphosphonates only)
Inability to stand or sit upright for at least 30-60 minutes
after taking the medication (caution applies to oral
bisphosphonates only)


Hypocalcaemia—correct this before starting oral or
intravenous treatment
Pregnancy or lactation
Severe renal impairment (creatinine clearance ≤30 mL/min for risedronate and ibandronate and ≤35 mL/min for alendronate and zoledronic acid). Renal impairment has been observed after the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction

Hypersensitivity to bisphosphonates or any of the

excipients.
Use caution in prescribing oral bisphosphonates to patients with
active or recent oesophageal or upper gastrointestinal problems.

In patients with known Barrett’s oesophagus consider the benefits and potential risks of alendronate on an individual patient basis.
Administration of intravenous bisphosphonates may be
associated with a self limiting influenza-like illness with fever, myalgia, arthralgia, and headache in ≥1/10 of patients. To reduce the incidence and severity of these symptoms, advise taking paracetamol or ibuprofen shortly after administration of the drug.

Patients with poor oral health who need dental extraction or other invasive dental procedures are at increased risk of osteonecrosis of the jaw, so refer these patients for expert dental assessment and treatment before starting bisphosphonates and,
if possible, avoid invasive dental procedures in patients already taking bisphosphonates.
Advise patients taking bisphosphonates to maintain good dental hygiene.

As patients taking bisphosphonates may rarely develop atypical fractures, consider imaging in those who develop hip, thigh, or groin pain. In the patients with a diagnosis of an atypical fracture, consider imaging of the contralateral femur.
Withdrawal of bisphosphonate treatment is advised in patients who develop osteonecrosis of the jaw or atypical fractures.


How cost effective are bisphosphonates?
Generic formulations of alendronate are now predominantly used (with a current NHS cost of £17.04 (€21; $27) a year). The cost effectiveness analysis conducted by NICE was conducted
when the annual price of alendronate was higher (£53.56) but showed its cost effectiveness in the secondary prevention of fracture in post-menopausal women aged ≥55 years with osteoporosis and in women aged 50-55 years in whom independent clinical risk factors for fracture were also present
(incremental cost effectiveness ratio (ICER) <£30 000 per quality adjusted life year).

For primary prevention, with an

ICER of £20 000 per quality adjusted life year as the threshold,
additional risk factors and/or lower BMD were needed,
depending on age.11 The analysis conducted by the National
Osteoporosis Guideline Group showed that alendronate at a cost
of £90 a year was cost effective in primary or secondary
prevention of fracture in post-menopausal women with
osteoporosis at any age and in women with a previous fragility
fracture, regardless of BMD (ICER <£20 000 per quality
adjusted life year).18
Generic versions of risedronate are also now available, although
they are currently more expensive than alendronate (NHS price
£19.51 a month).

How are bisphosphonates taken and monitored?

Ensure there are no contraindications to starting
bisphosphonates. Assess renal function and measure serum calcium concentration (and correct any existing hypocalcaemia) before starting oral or intravenous bisphosphonate treatment.
Check serum 25-hydroxyvitamin D concentrations in patients at risk of vitamin D deficiency (for example, if exposure to sunlight is low and in patients with malabsorption).


Treatment
for osteoporosis should include advice on lifestyle, nutrition, exercise, and measures to reduce falls. Coprescribe calcium and vitamin D supplements with bisphosphonates unless there is evidence of adequate dietary calcium intake and normal vitamin D status.
For Alendronate and risedronate are taken orally and are available in once daily or once weekly formulations. Ibandronate may be
taken orally as a once monthly dose or given as an intravenous injection once every three months.

Zoledronic acid is given as

an intravenous infusion once yearly.

As oral bisphosphonates may cause oesophageal irritation, advise patients to take the tablets on waking, with a large glass of water, and to sit upright or stand while taking the tablet and
not to lie down for at least 30 minutes (alendronate and risedronate) or 60 minutes (ibandronate) after taking it.
No food, drink, or other medications should be taken during this time.

Measurement of BMD is most commonly used to monitor bisphosphonate treatment. Some guidelines recommend measurement of BMD at intervals of one year or two years, although the value of this is uncertain and it may be sufficient
to measure BMD after three to five years of treatment.

If the patient’s BMD remains low and/or fracture has occurred during treatment, continue bisphosphonate treatment, but in other patients consider a “drug holiday” for two to three years.
If one or more fractures occur during treatment, check
compliance and exclude secondary causes of osteoporosis.
However, no treatment completely prevents fracture, so afracture during treatment does not necessarily mean lack of response.

How do bisphosphonates compare with

other drugs?
Other drugs approved for osteoporosis include denosumab, parathyroid hormone peptides, raloxifene, and strontium ranelate.
All these drugs reduce vertebral fractures, but only denosumab and strontium ranelate reduce non-vertebral fractures, including hip fractures.


The National Osteoporosis Guideline Group
considers denosumab, raloxifene, and strontium ranelate as second line agents for primary or secondary prevention of fracture in postmenopausal women.
Denosumab is administered once every six months by
subcutaneous injection. Strontium ranelate and raloxifene are taken orally once daily. Parathyroid hormone peptides are administered by daily subcutaneous injections.

Tips for prescribers

Do not prescribe oral bisphosphonates in patients with severe oesophageal disease or in those unable to comply with the dosing instructions.
Oral bisphosphonates are poorly absorbed and may cause oesophageal irritation, requiring patients to follow the administration instructions.

Treatment for osteoporosis should include not only drug treatment but also advice on lifestyle, nutrition, exercise, and measures to
reduce falls. Ensure adequate calcium intake and vitamin D status, prescribing supplements if needed
Encourage patients to report adverse effects such as gastrointestinal intolerance with oral agents as parenteral alternatives are available

As rare adverse effects are possible in long term users, after five years re-evaluate the need for continued treatment. Consider a “drug
holiday” for two to three years unless fracture has occurred during treatment or bone mineral density remains low

Tips for patients

Bisphosphonates are used in the treatment of osteoporosis to reduce the risk of having a fracture. They are given by mouth (once weekly or once monthly) or by injection (once every three months or once yearly). Calcium and vitamin D supplements are usually needed as well

When taken by mouth, the bisphosphonate tablet is taken first thing in the morning on an empty stomach with a large glass of water.
You should be sitting upright or standing when you take the tablet and must not lie down for at least 30 minutes afterwards (or 60 minutes if you’re taking ibandronate). No food, drink or other tablets should be taken during this time .
The most common side effects with bisphosphonate tablets are indigestion and heartburn. These are less likely to occur when the tablet is taken correctly, but if they occur you should contact your GP


Some people get a flu-like illness when bisphosphonates are given by injection. This usually lasts two to three days. A mild pain
reliever such as ibuprofen or paracetamol can reduce this side effect.
Very rarely, a condition called osteonecrosis of the jaw may develop in people taking bisphosphonates.

Before starting treatment, tell

your doctor if you have problems with your teeth or gums. During treatment, have regular dental check-ups and let your dentist know
that you are taking a bisphosphonate
If you develop hip, thigh or groin pain, see your doctor because, rarely, unusual fractures of the thigh bone develop in people taking
bisphosphonates and an x ray may be indicated

Bisphosphonates are usually given for three to five years in the first instance. After this time your doctor may do some tests to see if
you need to continue or if you can stop the treatment for two to three years. It is very important to take the treatment regularly, and if
for any reason you are unable to do this, you should contact your GP.