Bone Disease in CF Clinical Care Guidelines

Prevention, early recognition, and treatment of cystic fibrosis-related bone disease are imperative to sustain bone health. This guideline provides recommendations regarding screening and treatment to optimize bone health in people with CF.

Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP, Elkin SL, Guise TA, Hardin DS, Haworth CS, Holick MF, Joseph PM, O'Brien K, Tullis E, Watts NB, White TB. Guide to Bone Health and Disease in Cystic Fibrosis. J Clin Endocrinol Metab. 2005 Mar;90(3):1888-96. Epub 2004 Dec 21.PMID: 15613415

Cystic fibrosis-related bone disease is a common complication of CF and is characterized by low bone mineral density (BMD) and increased rates of fractures. A consensus conference convened by the Cystic Fibrosis Foundation in 2002 addressed pathogenesis, diagnosis, and treatment of bone disease in CF, and an updated review was published in 2005. An expert committee updated evidence grades, using relevant manuscripts published after 2005. Key clinical questions, however, remain unanswered.

Poor bone health in CF is likely a result of multiple factors, including malabsorption of fat-soluble vitamins, poor nutritional status, lack of physical activity, glucocorticoid therapy, delayed puberty, intermittent hypogonadism mainly due to chronic disease, and chronic lung inflammation. Prevention, early recognition, and treatment are imperative to sustain bone health to prevent pathological fractures and maintain the patient's quality of life. This guideline was developed to provide recommendations regarding screening and treatment to optimize bone health in people with CF.

Methodology

An expert committee reviewed and graded the available evidence and developed evidence-based and consensus recommendations to optimize bone health in people with CF. 

Evidence grades:

  • I: Evidence obtained from at least one properly randomized, controlled trial.
  • II-1: Evidence obtained from well-designed controlled trials without randomization.
  • II-2: Evidence obtained from well-designed cohort or case-controlled analytic studies, preferably from more than one center or research group.
  • III: Opinions of respected authorities based on clinical experience, descriptive studies, or reports from expert committees.

Recommendations

Screening
Recommendations Evaluation of the Evidence

Obtain dual x-ray absorptiometry (DXA) scan on all adults AND Children >8 years old if <90% Ideal Body Weight, FEV1 < 50% predicted, glucocorticoids of ≥ 5 mg/day for ≥ 90 days/year, delayed puberty, or a history of fracture

  
Treatment for DXA T/Z score ≥ -1.0
Recommendations Evaluation of the Evidence

Improve nutritional status:

  1. Optimize vitamin D2
    calcium3
    and vitamin K supplementation 3



Grade: III
Grade: II
Grade: II-1
  1. Achieve a target body mass index > 25th percentile
 Grade: II-1 
  1. Encourage outdoor weight-bearing exercise
 Grade: I 

Repeat DXA every five years

  
Treatment for DXA -1 > T/Z score > -2.0
Recommendations Evaluation of the Evidence

Improve nutritional status as above

  

Address potential pulmonary and endocrine pathology:

  
  1. Aggressive pulmonary infection treatment
 Grade: III
  1. Minimize steroid dosing
 Grade: I-II
  1. Treat CF-related diabetes4, delayed puberty, or hypogonadism5
 Grades: I-II
  1. Endocrine referral
  
  1. If fragility fractures have occurred, patient is awaiting transplant, or BMD loss is > 3-5 percent per year, start bisphosphonates
 Grades: I-III

Repeat DXA two to four years

  
Treatment for T/Z score ≤ -2.0
Recommendations Evaluation of the Evidence

Improve nutritional status as above

  

Address potential pulmonary and endocrine pathology as above

  

Consider bisphosphonates6

  
  1. Oral: Alendronate 70 mg weekly (or 10 mg daily)
 Grade: I
  • i. Risendronate 35 mg weekly (or 5 mg daily)
 Grade: I
  1. IV: Pamidronate 30 mg in 500 ml saline infused over three hours every three months
 Grade: I
  1. Zoledronic acid 4-5 mg infused over 15-20 minutes yearly 
 Grade: III
  1. Zoledronic acid 2 mg every three months for two years
 Grade: I

Annual DXA

  

1DXA scan: Gold standard. Use Z scores for children less than 18 years. T and Z scores are nearly equivalent between ages 18-30. Use T scores for ages 30 years or older.

2Vitamin D supplementation: Supplement preferably with vitamin D3 to target 25OHD concentrations of 30-60 ng/ml (75-150 nmol per liter) (Tanpricha et al; full reference cited in “Further Reading” section below).

3Calcium and vitamin K supplementation: Follow dietary reference intakes. Calcium: 1300-1500 mg (32-37 mmol) per day. Vitamin K supplementation 0.3-0.5 mg (1.7-2.9 nmol) per day (2 ADEKS)

4CF-related diabetes treatment: Follow CF-Related Diabetes Practice Guidelines.

5Delayed puberty or hypogonadism: Sex steroid replacement may prove to be beneficial, but risk-benefit ratio for hormonal replacement and complicated nature of CF bone disease makes individualization of therapy important.

6Bisphosphonate therapy: Pamidronate, zoledronic acid, and risedronate can be associated with bone pain. Oral alendronate has shown promise despite concerns that pancreatic insufficiency would limit absorption.

Unanswered Questions

Key clinical questions remain unanswered. Does BMD actually help to predict future fracture risk in adults and children? Does CFTR modulator therapy impact bone health?

The manuscripts below address these clinical questions:

Further Reading

Relevant manuscripts published after the original guidelines in 2005 are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

  1. Tangpricha V, Kelly A, Stephenson A, Maguiness K, Enders J, Robinson KA, Marshall BC, Borowitz D, for the Cystic Fibrosis Foundation Vitamin D Evidence-Based Review Committee. An update on the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from the Cystic Fibrosis Foundation. J Clin Endocrinol Metab. 2012;97(4):1082-93. Doi: 10.1210/jc.2011-3050. Epub 2012 Mar 7.PMID: 22399505
  2. Haworth CS, Sharples L, Hughes V, Elkin SL, Hodson ME, Conway SP, et al. Multicentre trial of weekly risendronate on bone density in adults with cystic fibrosis. J Cyst Fibros. 2011; 10(6): 470-6. Doi: 10.1016/j.jcf.2011.07.007. Epub 2011 Aug 16.PMID: 21849264
  3. Chapman I, Greville H, Ebeling PR, King SJ, Kotsimbos T, Nugent P, Player R, Topliss DJ, Warner J, Wilson JW. Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF). Clin Endocrinol (Oxf). 2009;70(6):838-46. Doi: 10.1111/j. 1365-2265.2008.03434.x. Epub 2008 Sept 24.PMID: 18823395
  4. Sermet-Gaudelus I, Castanet M, Retsch-Borgart G, Aris RM. Update on Cystic Fibrosis-Related Bone Disease: A Special Focus on Children. Paediatric Respiratory Reviews. 2009;10(3):134-142. Doi: 10.1016/j.prrv.2009.05.001.PMID: 19651384

This executive summary was prepared by:

Maria S. Rayas, M.D. (University of Texas Health Science Center San Antonio) and Robert M. Aris, M.D. (University of North Carolina)

The guidelines were published in March 2005, they were reviewed in April 2019 and it was determined that no update is needed at this time.

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