Endocrinology - intravenous bisphosphonate therapy
Main indications for bisphosphonate therapy in endocrinology are for conditions with primary or secondary osteoporosis with pathological fractures.
Background
Conditions with primary or secondary osteoporosis associated with pathological fractures.
General indications for Bisphosphonate therapy in Paediatric Endocrinology
Low bone density (BMD Z-score usually < -2.0*) AND any of the following
≥ 1 vertebral compression fractures
≥ 2 long bone fractures by 10 years old
≥ 3 long bone fractures by 19 years old
Significant fracture in low-tone (neuromuscular) or low-mobility condition (cerebral palsy) e.g. low trauma femur fracture in child with CP
Osteogenesis imperfecta with fractures
Non-osteoporotic conditions
Hypercalcaemia (Pamidronate at low dose, approx. 10 – 25% of normal dose). See Rheumatology guideline
Avascular necrosis and acute bone pain (in particular hips)
Other e.g. fibrous dysplasia with associated bone pain
*in some cases getting a DXA scan for BMD measurements is not technically feasible
Relative contraindications
Hypocalcaemia (serum adjusted calcium < 2.1 mmol/L). Correct prior to treatment (Hypocalcaemia guideline)
Untreated vitamin D deficiency (25(OH) <50 nmol/L). Correct prior to treatment (Vitamin D deficiency guideline)
Allergic reaction to bisphosphonates
Renal impairment . Dose reduction and caution to be used
Pregnancy (absolute contraindication)
Acute illness and fever. Defer until resolved
Ocular symptoms (uveitis or scleritis) . Review by Ophthalmology prior to any treatment
Pre Treatment, Monitoring and Post Treatment
Prior to Commencement of Bisphosphonate Therapy
Bedside dental examination prior to treatment to avoid the need for invasive dental procedures once treatment has commenced. Referral to a dentist should be considered especially if there is evidence of poor dentition prior to starting treatment.
Ophthalmology examination if has any ocular signs or symptoms (uveitis or scleritis)#
Consider pregnancy testing in adolescent girls#
Ensure the criteria for treatment (as above) are met and a plan for length of treatment has been set by the responsible Paediatric Endocrinologist.
Consider admitting all children having their first infusion and those who had complications with previous infusions including hypocalcaemia, discuss in advance with the SMO responsible. Subsequent infusions can be in Day Stay if first infusions tolerated well.
Bisphosphonate infusions should be scheduled early to mid-week (so calcium check 48 hours post-first infusion can be done by Friday and not over the weekend).
# Consider prior to all infusions, not just first infusion.
Pre Treatment Tests (7-14 days pre 1st infusion; within 3 months of subsequent infusions)
Full blood count
Calcium** (and albumin), PO4, Na, K
Liver function (including ALP)
Renal function**
25(OH) vitamin D**
PTH, Mg
Baseline PiNP if requested consultant/SMO (bone turnover marker) (used as a guide long term; result not needed to start bisphosphonate treatment).
**Discuss any concerns in relation to hypocalcaemia, low vitamin D, and renal impairment with the responsible SMO prior to starting any treatment.
Pre and Post Treatment Calcium & Vitamin D Supplementation
Pre Treatment
Consider oral calcium and vitamin D therapy in the 7 – 14 days prior to Zoledronate infusion. See Table 1.
Treat vitamin D deficiency while ensuring that calcium intake is adequate. For those with poor nutritional state suggestive of suboptimal dietary calcium consider supplementary calcium. The daily recommended intake of elemental calcium depends on age: 500 mg (1-3 years), 800 mg (4-8 years) and 1300 mg (9-18 years).
Post Treatment
Consider oral calcium and vitamin D supplementation (as below) for 7 days post-treatment as per Table 1.
Table 1: Calcium and Vitamin D Supplementation Pre and Post Bisphosphonate Infusions
| Indication | Medication | Dose | Duration | |
|---|---|---|---|---|
| PRE-INFUSION | ||||
| First infusion and/or Hypocalcaemia with previous infusions and/or Poor nutritional state | Calcium and ONE source of Vitamin D Calcium (100 mg calcium carbonate = 40 mg (1 mmol) elemental calcium) |
Multiple formulations available: please check eligibility criteria before prescribing (see information below) | For 7 days PRIOR to infusion | |
| Vitamin D deficiency (25OH vitamin D <50) | EITHER Cholecalciferol## (1.25 mg capsule contains 50,000 units) Preferred | 25,000 - 50,000 units as single dose (some will use higher dose) | Single dose 7-14 days PRIOR to infusion | |
| OR Calcitriol† | 0.03 - 0.06 micrograms/kg/day (max 1-2 micrograms/day) | Once daily for 7 days PRIOR to infusion | ||
| OR Alfacalcidol (One-Alpha⁺) | One-Alpha oral drops contain 2 micrograms/mL of alfacalcidol: dose is 0.05 microgram/kg/day | Once daily for 7 days POST infusion | ||
| POST-INFUSION | ||||
| First infusion^ and/or Hypocalcaemia* and/or Poor nutritional status | Calcium and ONE source of Vitamin D Calcium (see above) | 50-100 mg/kg/day elemental calcium in 2-4 divided doses (max 2500 mg/day) | For 7 days POST infusion | |
| AND Calcitriol† | 0.03 - 0.06 micrograms/kg/day (max 1-2 micrograms/day) | Once daily for 7 days POST infusion | ||
| OR Alfacalcidol (One-Alpha⁺) | One-Alpha oral drops contain 2 micrograms/mL of alfacalcidol: dose is 0.05 microgram/kg/day | Once daily for 7 days POST infusion | ||
## Cholecalciferol capsules (1.25 mg, 50,000 units) can be opened and mixed with oil or food for young children by either soaking in water and squeezing open or warming and cutting along the stitch line (are better absorbed in oil as fat soluble vitamin) or Puria (colecalciferol) drops for younger children or newborns (1 drop = 10 micrograms = 400 units of Vitamin D)
†Calcitriol capsules (0.25 and 0.5 microgram) are liquid filled capsules. If patient cannot swallow capsules patients may either use needle to extract the liquid or make holes and squeeze out liquid. Part doses are not possible.
*If adjusted calcium <1.9 mmol/L discuss with responsible SMO (see Hypocalcaemia guideline)
+Alfacalcidol (One-Alpha) consider for small children (normally <15 - 20 kg)
^Consider supplementation after every infusion depending on child's dietary calcium intake. Discuss with responsible SMO.
Elemental calcium formulations currently available in New Zealand
For children < 5 years old
Calcium effervescent tablets are funded on the community schedule and Hospital Medicines List (Subsidy by endorsement on prescription - for paediatric patients (< 5 years) where calcium carbonate oral liquid is considered unsuitable)
Cacit® 500 mg Calcium carbonate effervescent tablet: Each tablet contains 500 mg (12.5 mmol) elemental calcium (Please note this replaces Calsource® which contained 1000mg elemental calcium per tablet)
For children > 5 years old
Roxane® calcium carbonate liquid 500 mg / 5 mL liquid (Subsidy by endorsement on prescription for patients unable to swallow calcium carbonate tablets or where calcium carbonate tablets are inappropriate). Each mL contains 100 mg (2.5 mmol) elemental calcium
or
Arrow-Calcium® 1.25 g Calcium carbonate tablet (Fully subsidised in the community, no endorsement required). Each tablet contains 500 mg (12.5 mmol) elemental calcium.
Post Treatment
Predict they will have an acute phase reaction (APR), especially with the first few infusions, or if history of pain post previous infusions. Onset of APR symptoms is usually within 24 hours of infusion, lasting up to 48 – 72 hours and only 20% would be considered significant.
Use regular Ibuprofen 5-10 mg/kg every 6-8 hours (max 400 mg per dose) and paracetamol 15 mg/kg q6h (max 1g per dose)
Offer Ondansetron 0.1 – 0.2 mg/kg (round dose to nearest 1-2mg) up to 8 hourly (max 8 mg per dose) for nausea and/or vomiting, especially if on oral steroids (e.g. Duchenne’s on oral steroids).
Check calcium and albumin 24 - 48 hours after the zoledronate FIRST infusion (ideally 48 hours post infusion). Check after subsequent infusions if concerns.
Post-infusion asymptomatic hypocalcaemia (serum adjusted calcium <1.9 mmol/l) should be discussed with the responsible or on call SMO and consider discussion with the Paediatric Endocrinology service. Treatment with calcium and calcitriol may be indicated depending on the level and symptoms (see Hypocalcaemia guideline).
Symptomatic hypocalcaemia should prompt an admission under Paediatric Endocrinology
Zoledronate Dosage Guide
Zoledronate (Aclasta®) is potent inhibitor of osteoclastic bone resorption that improves bone mineral density. It is used in endocrinology primarily for children and adolescents with primary or secondary osteoporosis with pathological fractures. It is the most commonly used bisphosphonate agent due to its long action and short infusion time.
Zoledronate (Aclasta®) is available in a 5 mg/100 mL ready to infuse solution and is currently funded under special authority. The solution should be administered intravenously via a vented infusion line, given at a constant infusion rate. Infuse over at least 30 minutes.
Doses less than 0.5 mg may need to be diluted further for administration to enable the infusion to be administered over 15 minutes.
Please chart both the generic name Zoledronate and brand name Aclasta® on the medication chart to avoid confusion or incorrect dispensing of brand.
Observations, including temperature, pulse and respirations should be recorded hourly for the initial cycle and then 2 hourly for subsequent cycles.
Table 2: Dosage Guide for Zoledronate Infusions
| Indication | Drug | Infusion Number | Dose | Maximum Dose | Dosing Interval |
|---|---|---|---|---|---|
| Osteoporosis | Zoledronate (Aclasta®) | 1st | 0.0125 mg/kg | 0.5 – 1 mg | First infusion |
| 2nd | 0.0375 mg/kg | 1 mg | 6–8 weeks post 1st dose | ||
| 3rd onwards | 0.05 mg/kg | 2 mg | 6 months post 2nd dose then 6 monthly |
This is only a guide to dosing. Endocrinologists prescribe doses and frequency based on a patient’s individual needs.
NB: For OI (osteogenesis imperfecta and some infants) the established dosing is often 0.025 mg/kg 3 monthly. First infusion is therefore 0.0125 mg/kg, second infusion is 0.0125 mg/kg at 6-8 weeks, and then subsequent infusions 0.025 mg/kg/dose every 3 months.
For adolescents on once yearly 0.1 mg/kg infusions, the maximum dose is 5 mg per infusion.
Pamidronate
Pamidronate is generally only used rarely now in most centres (sometimes in the very young children with severe OI), however the length of infusion and repeated doses often require a central line; so many are therefore treated with IV Zoledronate in 3 monthly doses.
Pamidronate is our choice for Hypercalcaemia. Dosing for Chronic Recurrent Multifocal Osteomyelitis (CRMO) and Hypercalcaemia are as follows.
Starship Rheumatology IV Bisphosphonate Therapy (includes dosing and infusion guidelines)
Starship Hypercalcaemia in the Oncology Patient
Adverse effects
Bisphosphonates are generally well tolerated in children. Adverse effects generally dose dependent.
Acute phase reaction is common: Flu-like reaction or acute phase reaction (APR) with fever and/or arthralgia and myalgia (10-70%), most commonly occurs after the first bisphosphonate infusion, resolving within 48-72 hours.
Transient, usually asymptomatic, hypocalcaemia, hypophosphataemia and hyperparathyroidism have been reported. The risk may be reduced by ensuring the vitamin D levels are normal and calcium intake adequate, with subclinical hypoparathyroidism an additional potential risk factor.
Adverse effects reported in adult use of bisphosphonates including uveitis, thrombocytopenia and oesophageal or oral ulceration (oral agents used) are rare in children with no reports of avascular necrosis of the jaw in children or adolescents.
All intravenous bisphosphonates have the potential to cause acute tubular necrosis with the dose, frequency and speed of the infusion important determinants.
Length of Bisphosphonate therapy
Depends on underlying indication for bisphosphonate therapy and is decided on-going by the responsible Paediatric Endocrinologist.
Those children with underlying disorders that continue to adversely affect bone health e.g. osteogenesis imperfecta should continue infusions until completion of linear growth
To avoid metaphyseal fractures at junction of treated dense bone and the new (untreated) thinner bone after bisphosphonate discontinuation.
Consider more frequent lower dose bisphosphonate regimens in children with high bone turnover.
Reduce frequency of infusions for those on long term treatment with low bone turnover and markedly improved BMD, and reduced fractures.
Additional information
Links
Starship Child Health Individual Zoledronate Treatment Plans
To be printed off, filled out and put in patient’s clinical notesNZ Formulary for Children
Pharmac Special Authority
Consensus Guidelines on the Use of Bisphosphonate Therapy in Children and Adolescents 2018 http://www.ncbi.nlm.nih.gov/pubmed/29504223
Osteoporosis
In children and adolescents osteoporosis can be primary (due to intrinsic genetic skeletal defects) or secondary (as a result of underlying chronic illness, medication, malnutrition, immobility etc.).
BOTH low bone mineral density (DXA scan BMD Z-score ≤ -2.0) AND a significant fracture history are required to make the diagnosis of osteoporosis in children and adolescents. DXA Z-score ≤ -2.0 alone is not sufficient to make the diagnosis.
Vertebral fractures (rare in children and indicative of “pathology”)
≥ 1 vertebral compression (crush) fractures in the absence of local disease or high-energy trauma is indicative of osteoporosis*
Long bone fractures
A clinically significant fracture history + BMD Z-score ≤ -2.0 is indicative of osteoporosis**
Clinically significant fracture history =
≥ 2 long bone fractures by 10 years old
≥ 3 long bone fractures up to 19 years
Digit fractures, metatarsal fractures and 'greenstick' forearm fractures NOT included as long bone fractures
*Doing a DXA scan to measure BMD adds to the overall assessment of bone health but isn’t essential
**BMD Z-score > -2.0 does not preclude the possibility of skeletal fragility and increased fracture risk
Note: DXA scans aren’t practical/indicated for some children
Causes of Osteoporosis
| Primary (intrinsic skeletal defect of genetic origin) | Secondary |
|---|---|
Osteogenesis imperfecta (OI) - most common primary cause in children | Underlying chronic illness Chronic inflammation, hypoxia, renal or liver impairment, GH deficiency, delayed puberty, hypogonadism, hyperthyroidism, hyperparathyroidism, hypercortisolism, hyperparathyroidism, leukaemia, haemaglobinopathies, JIA, SLE Medication Glucocorticoids, antiepileptics, calcineurin inhibitors, anticoagulants, methotrexate, GnRH agonists Environmental/nutrition factors Limited sunlight exposure, inadequate calcium or vitamin D, malnutrition, malabsorption (e.g. Crohn’s, Coeliac disease, cystic fibrosis), eating disorders Immobility Limited weight bearing activity, muscle weakness, neurological impairment, neuromuscular disorders e.g. cerebral palsy, muscular dystrophy, spinal muscular atrophy, spinal cord injury Organ transplant, stem-cell transplant Prenatal factors, pre-term birth |
Bone Health
It is important to emphasize the benefits of conservative measures to optimize bone health
Physical activity that increases bone loading and muscle strength
Adequate vitamin D: sunlight, dietary +/- supplementation
Adequate calcium: dietary +/- supplementation
Use bone-sparing treatment options (when available) for underlying chronic conditions
Consider pubertal induction, if appropriate
Bisphosphonates (BPs)
Potent inhibitors of osteoclastic bone resorption
Prevent attachment of osteoclasts to bone surface, inhibit bone resorption and promote osteoclast apoptosis
The decreased bone resorption allows for new bone formation and increase in BMD
Have 2 phosphonate (PO(OH)2) groups therefore called bis- or di- + phosphonate
Chemical properties of each bisphosphonate determined by R-groups
| Zoledronate = Zoledronic Acid (Aclasta) | Pamidronate |
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