BNF 78 Disorders of bone metabolism 731
Dose adjustments Max. initial dose 1200 mg daily if eGFR
Use half normal dose if eGFR 10–30 mL/minute/1.73 m2
l MONITORING REQUIREMENTS Monitor renal function,
serum calcium and serum phosphate before and during
l DIRECTIONS FOR ADMINISTRATION Avoid food for 2 hours
supplements and antacids; maintain adequate fluid intake.
l PATIENT AND CARER ADVICE Patients or carers should be
given advice on how to administer sodium clodronate
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 10
Sodium clodronate 800 mg Bonefos 800mg tablets |
60 tablet P £146.43 DT = £146.43
▶ Loron (Intrapharm Laboratories Ltd)
Sodium clodronate 520 mg Loron 520mg tablets | 60 tablet P £114.44 DT = £114.44
▶ Sodium clodronate (Non-proprietary)
Sodium clodronate 400 mg Sodium clodronate 400mg capsules |
30 capsule P £34.96 | 120 capsule P £139.83 DT = £139.83
Sodium clodronate 400 mg Bonefos 400mg capsules | 120 capsule P £139.83 DT = £139.83
▶ Clasteon (Kent Pharmaceuticals Ltd)
Prevention of skeletal related events in advanced
malignancies involving bone (specialist use only)
▶ Adult: 4 mg every 3–4 weeks, calcium 500 mg daily and
vitamin D 400 units daily should also be taken
Tumour-induced hypercalcaemia (specialist use only)
Paget’s disease of bone (specialist use only)
▶ Adult: 5 mg for 1 dose, at least 500 mg elemental
calcium twice daily (with vitamin D) for at least 10 days
is recommended following infusion
Osteoporosis (including corticosteroid-induced
osteoporosis) in men and postmenopausal women
▶ Adult: 5 mg once yearly as a single dose, in patients
with a recent low-trauma hip fracture, the dose should
be given at least 2 weeks after hip fracture repair;
before first infusion give 50 000–125 000 units of
l CAUTIONS Atypical femoral fractures . cardiac disease
(avoid fluid overload). concomitant medicines that affect
l INTERACTIONS → Appendix 1: bisphosphonates
▶ Common or very common Appetite decreased . chills . flushing
▶ Rare or very rare Confusion . Fanconi syndrome acquired . pancytopenia
▶ Frequency not known Acute phase reaction
SIDE-EFFECTS, FURTHER INFORMATION Renal impairment
and renal failure have been reported; ensure patient is
hydrated before each dose and assess renal function.
l CONCEPTION AND CONTRACEPTION Contra-indicated in
women of child-bearing potential.
l PREGNANCY Avoid—toxicity in animal studies.
l BREAST FEEDING Avoid—no information available.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
severe hepatic impairment (limited information available).
l RENAL IMPAIRMENT Avoid in tumour-induced
hypercalcaemia if serum creatinine above
400 micromol/litre. Avoid in advanced malignancies
involving bone if eGFR less than 30 mL/minute/1.73 m2 (or
if serum creatinine greater than 265 micromol/litre). Avoid
in Paget’s disease, treatment of postmenopausal
osteoporosis and osteoporosis in men if eGFR less than
Dose adjustments In advanced malignancies involving
bone, if eGFR 50–60 mL/minute/1.73 m2 reduce dose to
3.5 mg every 3–4 weeks; if eGFR 40–50 mL/minute/1.73 m2
reduce dose to 3.3 mg every 3–4 weeks; if eGFR
30–40 mL/minute/1.73 m2 reduce dose to 3 mg every
3–4 weeks; if renal function deteriorates in patients with
bone metastases, withhold dose until serum creatinine
returns to within 10% of baseline value.
▶ Correct disturbances of calcium metabolism (e.g. vitamin
D deficiency, hypocalcaemia) before starting. Monitor
serum electrolytes, calcium, phosphate and magnesium.
▶ Monitor renal function in patients at risk, such as those
with pre-existing renal impairment, those of advanced
age, those taking concomitant nephrotoxic drugs or
diuretics, or those who are dehydrated.
l DIRECTIONS FOR ADMINISTRATION
▶ When used for Prevention of skeletal related events in advanced
malignancies involving bone or Tumour-induced
hypercalcaemia For intravenous infusion, infuse over at least
15 minutes; administer as a single intravenous solution in
a separate infusion line. If using 4 mg/5 mL concentrate for
solution for infusion or preparing a reduced dose of
4 mg/100 mL solution for infusion for patients with renal
impairment, dilute requisite dose according to product
▶ When used for Paget’s disease of bone or Osteoporosis (including
corticosteroid-induced osteoporosis) in men and postmenopausal
women For intravenous infusion, give via a vented infusion
line over at least 15 minutes.
l PATIENT AND CARER ADVICE A patient reminder card
should be provided (risk of osteonecrosis of the jaw).
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Bisphosphonates for treating osteoporosis (updated February
This technology appraisal guidance should be applied
clinically in conjunction with:
. NICE guideline on assessing the risk of fragility fractures
(CG146), which defines who is eligible for osteoporotic
. NICE quality standard on osteoporosis (QS149), which
defines the clinical intervention thresholds for the
10-year fracture probability of a major osteoporotic
fracture, in those patients who have undergone fracture
732 Disorders of bone metabolism BNF 78
Zoledronic acid is recommended as an option for treating
osteoporosis in patients, only if:
. the person is eligible for risk assessment as defined in
the full NICE guideline on osteoporosis, and
. the 10-year probability of osteoporotic fragility fracture
. the 10-year probability of osteoporotic fragility fracture
is at least 1% and the person has difficulty taking oral
bisphosphonates (alendronic acid, ibandronic acid or
risedronate sodium) or these drugs are contra-indicated
Patients whose treatment was started within the NHS
before this guidance was published should have the option
to continue treatment, without change to their funding
arrangements, until they and their NHS clinician consider
www.nice.org.uk/guidance/ta464
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (May 2003)
that zoledronic acid (Zometa ®) is accepted for restricted
use within NHS Scotland for the prevention of skeletal
related events in patients with breast cancer and multiple
myeloma if prescribed by an oncologist.
The Scottish Medicines Consortium has advised (October
2006) that zoledronic acid (Aclasta ®) is accepted for use
within NHS Scotland for the treatment of Paget’s disease
of bone in patients for whom the use of a bisphosphonate
The Scottish Medicines Consortium has advised (March
2008) that zoledronic acid (Aclasta ®) is accepted for
restricted use within NHS Scotland for the treatment of
osteoporosis in postmenopausal women in those for whom
oral treatment options for osteoporosis are inappropriate,
when initiated by a specialist.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Zoledronic acid (Non-proprietary)
Zoledronic acid (as Zoledronic acid monohydrate) 40 microgram
per 1 ml Zoledronic acid 4mg/100ml infusion bags | 1 bag P £174.14 (Hospital only) | 1 bag P £150.00
Zoledronic acid (as Zoledronic acid monohydrate) 50 microgram
per 1 ml Zoledronic acid 5mg/100ml infusion bags | 1 bag P £217.68 (Hospital only)
▶ Aclasta (Novartis Pharmaceuticals UK Ltd)
Zoledronic acid (as Zoledronic acid monohydrate) 50 microgram
per 1 ml Aclasta 5mg/100ml infusion bottles | 1 bottle P £253.38
Zoledronic acid (as Zoledronic acid monohydrate) 40 microgram
per 1 ml Zerlinda 4mg/100ml infusion bags | 1 bag P £150.00
▶ Zometa (Novartis Pharmaceuticals UK Ltd)
Zoledronic acid (as Zoledronic acid monohydrate) 40 microgram
per 1 ml Zometa 4mg/100ml infusion bottles | 1 bottle P £174.14
▶ Zoledronic acid (Non-proprietary)
Zoledronic acid (as Zoledronic acid monohydrate) 40 microgram
per 1 ml Zoledronic acid 4mg/100ml solution for infusion vials |
Zoledronic acid (as Zoledronic acid monohydrate) 50 microgram
Zoledronic acid (as Zoledronic acid monohydrate)
800 microgram per 1 ml Zoledronic acid 4mg/5ml concentrate for
Zoledronic acid 4mg/5ml solution for infusion vials | 1 vial P £91.95
▶ Zometa (Novartis Pharmaceuticals UK Ltd)
Zoledronic acid (as Zoledronic acid monohydrate)
800 microgram per 1 ml Zometa 4mg/5ml solution for infusion vials
CALCIUM REGULATING DRUGS › BONE
▶ BY SUBCUTANEOUS INJECTION, OR BY INTRAMUSCULAR
▶ Adult: 100 units every 6–8 hours (max. per dose
400 units every 6–8 hours), adjusted according to
▶ Adult: Up to 10 units/kg, in severe or emergency cases,
to be administered by slow intravenous infusion over at
▶ BY SUBCUTANEOUS INJECTION, OR BY INTRAMUSCULAR
▶ Adult: 100 units daily, adjusted according to response
for maximum 3 months (6 months in exceptional
circumstances), a minimum dosage regimen of 50 units
three times a week has been shown to achieve clinical
Prevention of acute bone loss due to sudden immobility
▶ BY SUBCUTANEOUS INJECTION, OR BY INTRAMUSCULAR
▶ Adult: Initially 100 units daily in 1–2 divided doses,
then reduced to 50 units daily at the start of
mobilisation, usual duration of treatment is 2 weeks;
l CONTRA-INDICATIONS Hypocalcaemia
l CAUTIONS Heart failure . history of allergy (skin test
advised).risk of malignancy—avoid prolonged use (use
lowest effective dose for shortest possible time)
l INTERACTIONS → Appendix 1: calcitonin (salmon)
(long term use).taste altered . vomiting
▶ Uncommon Hypersensitivity . hypertension . influenza like
illness . oedema . polyuria . skin reactions . visual
▶ Rare or very rare Bronchospasm .throat swelling .tongue
▶ Frequency not known Hypocalcaemia .tremor
l PREGNANCY Avoid unless potential benefit outweighs risk
l BREAST FEEDING Avoid; inhibits lactation in animals.
l RENAL IMPAIRMENT Use with caution.
l DIRECTIONS FOR ADMINISTRATION
▶ With intravenous use For intravenous infusion, give
intermittently in Sodium chloride 0.9%. Diluted solution
given without delay. Dilute in 500 mL give over at least
6 hours; glass or hard plastic containers should not be
used; some loss of potency on dilution and administration.
BNF 78 Disorders of bone metabolism 733
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Calcitonin (salmon) (Non-proprietary)
Calcitonin (salmon) 50 unit per 1 ml Calcitonin (salmon)
50units/1ml solution for injection ampoules | 5 ampoule P £167.50 DT = £167.50
Calcitonin (salmon) 100 unit per 1 ml Calcitonin (salmon)
100units/1ml solution for injection ampoules | 5 ampoule P £220.00 DT = £220.00
Calcitonin (salmon) 200 unit per 1 ml Calcitonin (salmon)
400units/2ml solution for injection vials | 1 vial P £352.00 DT =
CALCIUM REGULATING DRUGS › PARATHYROID
Treatment of osteoporosis in postmenopausal women and
in men at increased risk of fractures | Treatment of
corticosteroid-induced osteoporosis
▶ Adult: 20 micrograms daily for maximum duration of
treatment 24 months (course not to be repeated)
l CONTRA-INDICATIONS Bone metastases . hyperparathyroidism . metabolic bone diseases . Paget’s
disease . pre-existing hypercalcaemia . previous radiation
therapy to the skeleton . skeletal malignancies . unexplained raised alkaline phosphatase
▶ Rare or very rare Oedema .renal impairment
l RENAL IMPAIRMENT Caution in moderate impairment;
l PRESCRIBING AND DISPENSING INFORMATION Teriparatide
is a biological medicine. Biological medicines must be
prescribed and dispensed by brand name, see Biological
medicines and Biosimilar medicines, under Guidance on
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Raloxifene and teriparatide for the secondary prevention of
osteoporotic fragility fractures in postmenopausal women
(updated February 2018) NICE TA161
Teriparatide is recommended as an alternative treatment
option for the secondary prevention of osteoporotic
fragility fractures in postmenopausal women:
. who are unable to take alendronate and risedronate, or
have a contra-indication to or are intolerant of
alendronate and risedronate, or have had an
unsatisfactory response to treatment with alendronate
. who are 65 years or older and have a T-score of -4
standard deviations (SD) or below, or a T-score of -3.5
SD or below plus more than two fractures, or who are
aged 55-64 years and have a T-score of -4 SD or below
Women who are currently receiving treatment, but for
whom treatment would not have been recommended,
should have the option to continue treatment until they
and their NHS clinician consider it appropriate to stop.
www.nice.org.uk/guidance/ta161
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Forsteo (Eli Lilly and Company Ltd)
Teriparatide 250 microgram per 1 ml Forsteo
20micrograms/80microlitres solution for injection 2.4ml pre-filled pen
| 1 pre-filled disposable injection P £271.88 DT = £271.88
DRUGS AFFECTING BONE STRUCTURE AND
MINERALISATION › MONOCLONAL ANTIBODIES
l DRUG ACTION Denosumab is a human monoclonal
antibody that inhibits osteoclast formation, function, and
survival, thereby decreasing bone resorption.
Osteoporosis in postmenopausal women and in men at
increased risk of fractures | Bone loss associated with
hormone ablation in men with prostate cancer at
increased risk of fractures | Bone loss associated with
long-term systemic glucocorticoid therapy in patients at
▶ Adult: 60 mg every 6 months, supplement with calcium
and Vitamin D, to be administered into the thigh,
Prevention of skeletal related events in patients with
▶ Adult: 120 mg every 4 weeks, supplementation of at
least calcium 500 mg and Vitamin D 400 units daily
should also be taken unless hypercalcaemia is present,
to be administered into the thigh, abdomen or upper
Giant cell tumour of bone that is unresectable or where
surgical resection is likely to result in severe morbidity
▶ Adult: 120 mg every 4 weeks, give additional dose on
days 8 and 15 of the first month of treatment only,
supplementation of at least calcium 500 mg and
Vitamin D 400 units daily should also be taken unless
hypercalcaemia is present, to be administered into the
MHRA/CHM ADVICE: DENOSUMAB: ATYPICAL FEMORAL
Atypical femoral fractures have been reported rarely in
patients receiving denosumab for the long-term
treatment (2.5 or more years) of postmenopausal
Patients should be advised to report any new or
unusual thigh, hip, or groin pain during treatment with
Discontinuation of denosumab in patients suspected
to have an atypical femoral fracture should be
considered after an assessment of the benefits and risks
734 Disorders of bone metabolism BNF 78
MHRA/CHM ADVICE: DENOSUMAB: MINIMISING THE RISK OF
OSTEONECROSIS OF THE JAW; MONITORING FOR
HYPOCALCAEMIA—UPDATED RECOMMENDATIONS (SEPTEMBER
2014) AND DENOSUMAB: OSTEONECROSIS OF THE JAW—FURTHER
MEASURES TO MINIMISE RISK (JULY 2015)
Denosumab is associated with a risk of osteonecrosis of
the jaw (ONJ) and with a risk of hypocalcaemia.
Osteonecrosis of the jaw Osteonecrosis of the jaw is
a well-known and common side-effect in patients
receiving denosumab 120 mg for cancer. Risk factors
include smoking, old age, poor oral hygiene, invasive
dental procedures (including tooth extractions, dental
implants, oral surgery), comorbidity (including dental
disease, anaemia, coagulopathy, infection), advanced
cancer, previous treatment with bisphosphonates, and
to head and neck). The following precautions are now
recommended to reduce the risk of ONJ:
Denosumab 120 mg (cancer indication)
. A dental examination and appropriate preventative
dentistry before starting treatment are now
. Do not start denosumab in patients with a dental or
jaw condition requiring surgery, or in patients who
have unhealed lesions from dental or oral surgery
Denosumab 60 mg (osteoporosis indication)
. Check for ONJ risk factors before starting treatment. A
dental examination and appropriate preventative
dentistry are now recommended for patients with risk
All patients should be given a patient reminder card and
informed of the risk of ONJ. Advise patients to tell their
doctor if they have any problems with their mouth or
teeth before starting treatment, if they wear dentures
they should make sure their dentures fit properly before
starting treatment, to maintain good oral hygiene,
receive routine dental check-ups during treatment, and
immediately report any oral symptoms such as dental
mobility, pain, swelling, non-healing sores or discharge
to a doctor and dentist. Patients should tell their doctor
and dentist that they are receiving denosumab if they
need dental treatment or dental surgery.
Hypocalcaemia Denosumab is associated with a risk
of hypocalcaemia. This risk increases with the degree of
renal impairment. Hypocalcaemia usually occurs in the
first weeks of denosumab treatment, but it can also occur
Plasma-calcium concentration monitoring is
recommended for denosumab 120 mg (cancer
. within two weeks after the initial dose
. if suspected symptoms of hypocalcaemia occur
. consider monitoring more frequently in patients with
risk factors for hypocalcaemia (e.g. severe renal
impairment, creatinine clearance less than
Plasma-calcium concentration monitoring is
recommended for denosumab 60 mg (osteoporosis
. within two weeks after the initial dose in patients with
risk factors for hypocalcaemia (e.g. severe renal
impairment, creatinine clearance less than
. if suspected symptoms of hypocalcaemia occur
All patients should be advised to report symptoms of
hypocalcaemia to their doctor (e.g. muscle spasms,
twitches, cramps, numbness or tingling in the fingers,
MHRA/CHM ADVICE: DENOSUMAB: REPORTS OF OSTEONECROSIS
OF THE EXTERNAL AUDITORY CANAL (JUNE 2017)
Osteonecrosis of the external auditory canal has been
reported with denosumab and this should be considered
in patients who present with ear symptoms including
chronic ear infections or in those with suspected
cholesteatoma. Possible risk factors include steroid use
and chemotherapy, with or without local risk factors
such as infection or trauma. The MHRA recommends
advising patients to report any ear pain, discharge from
the ear, or an ear infection during denosumab treatment.
MHRA/CHM ADVICE: DENOSUMAB (XGEVA ®) FOR GIANT CELL
TUMOUR OF BONE: RISK OF CLINICALLY SIGNIFICANT
HYPERCALCAEMIA FOLLOWING DISCONTINUATION (JUNE 2018)
Cases of clinically significant hypercalcaemia (rebound
hypercalcaemia) have been reported up to 9 months
after discontinuation of denosumab treatment for giant
cell tumour of bone. The MHRA recommends that
prescribers should monitor patients for signs and
symptoms of hypercalcaemia after discontinuation,
consider periodic assessment of serum calcium, reevaluate the patient’s calcium and vitamin D
supplementation requirements, and advise patients to
report symptoms of hypercalcaemia.
Denosumab is not recommended in patients with
MHRA/CHM ADVICE: DENOSUMAB (XGEVA ®) FOR ADVANCED
MALIGNANCIES INVOLVING BONE: STUDY DATA SHOW NEW
PRIMARY MALIGNANCIES REPORTED MORE FREQUENTLY
COMPARED TO ZOLEDRONIC ACID (ZOLEDRONATE) (JUNE 2018)
A pooled analysis has shown an increased rate of new
primary malignancies in patients given Xgeva ® (1-year
cumulative incidence 1.1%) compared with those given
zoledronic acid (0.6%), when used for the prevention of
skeletal-related events with advanced malignancies
involving bone. No treatment-related pattern in
individual cancers or cancer groupings were apparent.
l CONTRA-INDICATIONS Hypocalcaemia
XGEVA ® Unhealed lesions from dental or oral surgery
▶ Uncommon Cellulitis (seek prompt medical attention). hypercalcaemia (on discontinuation)
▶ Rare or very rare Atypical femur fracture . osteonecrosis
l CONCEPTION AND CONTRACEPTION Ensure effective
contraception in women of child-bearing potential, during
treatment and for at least 5 months after stopping
l PREGNANCY Manufacturer advises avoid—toxicity in
animal studies; risk of toxicity increases with each
l BREAST FEEDING Manufacturer advises avoid.
l RENAL IMPAIRMENT Increased risk of hypocalcaemia if
creatinine clearance less than 30 mL/minute.
l MONITORING REQUIREMENTS Correct hypocalcaemia and
vitamin D deficiency before starting. Monitor plasmacalcium concentration during therapy.
Atypical femoral fractures Patients should be advised to
report any new or unusual thigh, hip, or groin pain during
Osteonecrosis of the jaw All patients should be informed to
maintain good oral hygiene, receive routine dental checkBNF 78 Disorders of bone metabolism 735
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