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Child Health Guideline Identifier

Rheumatology - intravenous bisphosphonate therapy

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Background

Chronic non bacterial osteomyelitis (CNO) or Chronic Recurrent Multifocal Osteomyelitis (CRMO) are non infectious inflammatory disorders affecting predominantly children and adolescents. While most symptoms resolve after puberty, it is estimated that approximately 25% will have ongoing disease or associated complications2 and up to 60% of children evolve or resemble spondyloarthropathies1. Non steroidal anti inflammatories are the commonly used first line treatment. Second line therapy includes corticosteroids, methotrexate, sulfasalazine, anti TNF agents and bisphosphonates. These may be applied in a step wise fashion with bisphosphonates generally reserved for those with severe disease, with involvement of the spine or hip or refractory disease1. However, there are currently no controlled trials comparing different drug therapies for CRMO3 and treatment strategies are based on retrospective data. Bisphosphonates like zoledronate, pamidronate and alendronate work by affecting bone metabolism through the osteoclast function.

Indications in Paediatric Rheumatology

  • CNO or CRMO resistant to steroid therapy or if vertebral or hip involvement
  • SAPHO (Synovitis, Acne, Pustulosis, Hyperosteosis and Osteitis)
  • Steroid induced osteoporosis or fractures

Relative contraindications

  • Hypocalcaemia (serum calcium < 2.1 mmol/l)
  • Untreated vitamin D deficiency (25(OH) <50, See Vitamin D deficiency - investigation and management)
  • Allergic reaction to bisphosphonates
  • Caution should be exercised with renal impairment, and doses should be adjusted
  • Pregnancy (absolute contra-indication)
  • Acute illness and fever
  • Ocular symptoms (uveitis or scleritis)

Pre Treatment, Monitoring and post treatment

Prior to commencement10, 12

  1. 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 with evidence of poor dentition.
  2. Ophthalmology examination with ocular symptoms (uveitis or scleritis)
  3. Consider pregnancy testing in adolescent girls

Pre-treatment testing (7-14 days prior to infusion)10, 12, 13

  1. Full blood count
  2. Electrolytes: Calcium (and albumin), PO4, Na, K+
  3. Liver function (including ALP)
  4. Renal function
  5. 25(OH) vitamin D and parathyroid hormone
  6. Discuss children with hypocalcaemia or subclinical hypoparathyroidism with the responsible consultant.

Consider regular calcium for 7 days prior to the first Zoledronate infusion, hypocalcaemia with previous bisphosphonate infusions or poor nutritional status. Treat vitamin D deficiency while ensuring that calcium intake is adequate and for those with poor nutritional state suggestive of suboptimal dietary calcium consider supplementary calcium. The daily recommended intake of calcium depends on age: 500mg (1-3 years), 800mg (4-8 years) and 1300mg (9-18 years)14.

Indication Medication Dose
Duration
First Bisphosphonate infusion* Calsource (1 tablet contains 1000mg of calcium) 50mg/kg/day calcium
Divided doses (maximum 2,500mg)
7 days prior to infusion
Vitamin D deficiency (25-hydroxyvitamin D < 50nmol/L) Cholecalciferol
(1.25mg capsules contain 50,000 IU)#
25,000 - 50,000 IU 7-14 days prior to infusion
  OR Calcitriol 0.03 - 0.06 mcg/kg/day (max 1-2 mcg/day) 7 days prior to infusion

*Consider with previous bisphosphonate infusion hypocalcaemia or poor nutritional status
# Cholecalciferol capsules (1.25mg, 50,000 IU) may be soaked in water and squeezed open or warmed and cut along the stitch line for young children
Only available in 0.25 and 0.5 microgram liquid filled capsules. If patient cannot swallow capsules patients may either use needles to extract the liquid or make holes and squeeze out liquid. Part doses are not possible.

  • All children should have bisphosphonate infusions early in the working week
  • All children having their first infusion or with previous complications including hypocalcaemia should be discussed in advance with the Endocrinology service and admitted for 48 hours to ensure the infusion is tolerated
  • All children should have a tailored treatment plan at the beginning of therapy. This should outline the type of bisphosphonate used, initial duration of therapy and timing of clinical review and further imaging to help determine radiographic and clinical remission

Post treatment13

  1. Check calcium and albumin 48 hours after the infusion.
  2. Asymptomatic hypocalcaemia (serum calcium <1.9mmol/l) should be discussed with the responsible or on call consultant and consider discussion with the Endocrinology service. Treatment with calcium and calcitriol maybe indicated depending on the level and symptoms (see Hypocalcaemia guideline).
  3. Symptomatic hypocalcaemia should prompt an admission under Endocrinology
  4. Consider regular calcium and vitamin D for 7 days if hypocalcaemia with previous bisphosphonate infusions.
  5. Ibuprofen 5-10mg/kg every 6-8 hours (maximum 400mg per dose) if required for acute phase reaction or bone pain.

Post infusion therapy with hypocalcaemia, vitamin D deficiency or poor nutritional status*

Medication Dose Duration
Calsource (1 tablet contains 1000mg of calcium) 50mg/kg/day calcium in divided doses (maximum 2,500mg) 7 days post infusion
Calcitriol 0.03 - 0.06 mcg/kg/day (max 1-2 mcg/day) 7 days post infusion

*If calcium <1.9 then discuss with responsible consultant (see hypocalcaemia protocol) and reduce dose in children aged less than 4 years

Ongoing Monitoring10, 12

  • Consider a dental examination with evidence of poor dentition
  • Consider further imaging (MRI with gadolinium preferred) every 1-2 years depending on clinical response for CNO/CRMO.
  • Consider bone density scan in 2 years in steroid induced osteoporosis.

Dosage and Administration

Availability

Pamidronate is available in 30mg, 60mg and 90mg vials without restriction. Zoledronate (Aclasta) is available in a 5mg/100ml suspension with no provision for CRMO or CNO on the Hospital Medicines list or Special Authority. However, while some children may qualify in the context of pathological fracture, significant osteopenia with or without background steroid use a Named Patient Pharmaceutical Assessment (NPPA) may be required.

Dosage

Pamidronate

There is no consensus on the dosage and duration of treatment of CNO or CRMO with some strategies adapted from Pamidronate use for Osteogenesis Imperfecta (OI)3. Suggested clinical application would include 3-day cycles every 3 months for those with vertebral abnormalities2 or consideration of an initial 3-day cycle followed by monthly single or 3 monthly 3-day therapy for 6 months in all others refractory to conventional therapy3,4.

Vertebral involvement 3-day therapy (0.5mg/kg, 1mg/kg and 1mg/kg) every 3 months
CRMO refractory to standard therapy 3-day initial therapy followed by 3-day therapy every 3 months or 1mg/kg single dose monthly for 6 months

*maximum daily dose 60mg/day and annual dose 11.5mg/kg/year

Pamidronate should always be diluted and administered by slow intravenous infusion in sodium chloride 0.9% or glucose 5%11. Below is the suggested infusion dilution in children over two years of age:

Child's weight (kgs) Pamidronate Dose (mg/dose) Volume of 0.9% NaCl to dilute dose
(administer over 4 hours)
 5 - 15 5 - 15 250ml
15 - 25 15 - 25 250ml
25 - 35 25 - 35 500ml
35 - 45 35 - 45 500ml
45 - 55 45 - 55 500ml
55 - 65 55 - 65 1000ml
65 - 75 65 -75 1000ml


Zoledronate13

There is no consensus regarding dosing for children with OI or other metabolic bone disorders with a single paper outlining a suggested treatment protocol for Zoledronate use in children with CRMO13. Lower doses for subsequent infusions may need to be considered if previous hypocalcaemia.

Indication Initial dose Subsequent doses Maximum single dose  Dosing interval
CRMO*, AVN, fibrous dysplasia 0.0125 mg/kg  0.025-0.05mg/kg  4mg  3-12 months 

*Test dose 0.0125mg/kg, 3 monthly dose 0.025mg/kg, 6 monthly dose 0.05mg/kg and yearly dose 0.1mg/kg.

Zoledronate should be diluted in 50ml of isotonic saline solution (0.9% sodium chloride) and given over 30-45 minutes10.

Observations, including temperature, pulse and respirations should be recorded hourly for the initial cycle and then 2 hourly for subsequent cycles.

Adverse effects

Bisphosphonates are generally well tolerated in children. Adverse effects generally dose dependent2,3.

  1. Flu-like reaction or acute phase reaction (APR) with fever and/or arthralgia and myalgia (10-70%), most commonly occurs after the first Pamidronate infusion, resolving within 48-72 hours2,3. Similarly, the risk is higher with the first Zoledronate infusion and in those who are bisphosphonate naïve13. Management consists of supportive and symptomatic treatment with non steroidal anti inflammatories in addition to excluding other causes of fever in immunosuppressed patients9. Administration of half the Pamidronate dose for the first infusion may reduce these symptoms9.
  2. Injection site reactions have been documented at a rate of 6% with a 2 hour infusion time6.
  3. 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 adequate9 with subclinical hypoparathyroidism an additional potential risk factor10.

Adverse effects reported in adult use of bisphosphonates including uveitis, thrombocytopenia and oesophageal or oral ulceration are rare in children with no reports of avascular necrosis of the jaw in children or adolescents8. All intravenous bisphosphonates have the potential to cause acute tubular necrosis with the dose, frequency and speed of the infusion important determinants5.

Information for Families

  1. CRMO:http://www.aboutkidshealth.ca/En/HealthAZ/ConditionsandDiseases/InflammatoryConditions/Pages/Chronic-Recurrent-Multifocal-Osteomyelitis-CRMO.aspx AND http://autoinflammatory.org/crmo.php
  2. Pamidronate:http://www.aboutkidshealth.ca/En/HealthAZ/Drugs/Pages/Pamidronate.aspx
  3. Bisphosphonates:https://rheumatology.org.au/patients/documents/Bisphosphonates_IV_2014_003.pdf

References

  1. Hedrich et al. Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatric Rheumatology 2013, 11:47
  2. Hospach T et al. Spinal Involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate. Eur J Pediatr (2010) 169:1105-1111.
  3. Mitteunen et al. Dramatic pain relief and resolution of bone inflammation flowing pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatric Rheumatology 2009, 7:2
  4. Hofmann et al. A standardised clinical and radiographic follow-up of patients with chronic non-bacterial osteomyelitis with pamidronate. Clinical and Experimental Rheumatology 2014; 32:604-609
  5. Diel et al. Adverse effects of bisphosphonates: current issues. The Journal of Supportive Oncology. Vol 5 (10); 475-482.
  6. Body, J. Dosing regimens and main adverse events of bisphosphonates. Seminars in oncology. Vol 28, No 4, Suppl 11 (august), 2001; pp 49-53.
  7. Ann Oncol (June 2006) 17 (6): 897-907.
  8. Bachrach L and Ward L. Clinical review: Bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab. February 2009, 94 (2):400-409. (?remove)
  9. Ward LM, Petryk A and Gordon C. Use of bisphosphonates in the treatment of pediatric osteoporosis. Int. J. Clin. Rheumatol. (2009) 4(6), 657-672.
  10. Barconcelli G and Bertelloni S. The use of bisphosphonates in paediatrics. Horm Res Paediatr 2014;82:290-302.
  11. PNM group. Pamidronate. New Zealand Data Sheet.
  12. Bhatt RN, Bibbert SA and Munns CF. The use of bisphosphonates in children: review of the literature and guidelines for dental management. Australian Dental Journal 2014; 59: 9-19.
  13. George S et al. Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience. J Clin Endocrinol Metab, November 2015, 100 (11):4163-4171
  14. Uziel Y, Zifman E and Philip H. Osteoporosis in children: pediatric and pediatric rheumatology perspective: a review. Pediatric Rheumatology 2009, 7:16.

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Document Control

  • Date first published: 07 June 2017
  • Date last published: 07 June 2017
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Rheumatology
  • Author(s): Paediatric Rheumatology
  • Owner: Paediatric Rheumatology
  • Editor: Greg Williams

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