What is the role of bisphosphonates in the treatment of osteogenesis imperfecta (OI)?

Updated: Feb 24, 2020
  • Author: Manoj Ramachandran, MBBS, MRCS, FRCS; Chief Editor: Harris Gellman, MD  more...
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Bisphosphonates (eg, pamidronate) are synthetic analogues of pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite. As a result, unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness.

Cyclic intravenous (IV) pamidronate is commonly given in a dosage of 7.5 mg/kg/y at 4- to 6-month intervals. [29, 30] Dosages have ranged from 4.5 to 9 mg/kg/y, depending on the protocol used. Cyclic administration of IV pamidronate reduces the incidence of fracture and increases bone mineral density (BMD), while reducing pain and increasing energy levels. [31] Current evidence does not support the use of oral bisphosphonates in patients with OI.

IV pamidronate is effective in babies and can be used to relieve pain in severe cases. Good evidence suggests that bisphosphonate therapy may significantly improve the natural history of type III and type IV disease, particularly by decreasing the rate of fracture, increasing BMD, decreasing bone pain, and significantly increasing height (especially with prolonged cyclic therapy up to 4 years). [32] In some cases, crumpled femurs and flattened vertebrae may assume more normal shapes and cortical thickness.

Adverse effects of pamidronate include an acute febrile reaction, mild hypocalcemia, leukopenia, a transient increase in bone pain, and scleritis with or without anterior uveitis. With milder forms of OI, the indications for bisphosphonate therapy have yet to be evaluated.

Other bisphosphonates (eg, risedronate, alendronate, [33] and zoledronic acid) are also being assessed. Alendronate was found to decrease predicted material properties and to have detrimental effects on osteoblasts and bone formation in mice with OI. A study from China found that long-term (3 years) alendronate therapy significantly lowered the incidence of fractures, increased BMD in the lumbar spine and femoral neck, and reduced bone turnover biomarkers in children and adolescents with OI. [34]  Risedronate may have some effect in reducing fractures in patients with OI. [35]

In a retrospective chart review and analysis aimed at determining the safety and efficacy of pamidronate therapy in 18 children younger than 24 months who had OI (mean age at treatment, 12 months), Kusumi et al found that mean lumbar z score improved from –3.63 at baseline to –1.53 at 1 year and to 0.79 by study end, whereas fracture rate improved from 0.32 fractures/patient-month before treatment to 0.03 fractures/patient-month after treatment. [36] Height standard deviation score was conserved from baseline to study end.

Hald et al conducted a metanalysis of six placebo-controlled trials, involving 424 patients with 751 patient-years of follow-up, to determine the effects of bisphosphonate therapy on fracture risk for patients with OI. [37] They found that the proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy and concluded that the effects of bisphosphonates on fracture prevention in OI are inconclusive.

A Cochrane review concluded that whereas oral or IV bisphosphonates increase BMD in children and adults with OI, these agents do not differ significantly from each other in this respect, and they have not been clearly shown to decrease fractures consistently. [38]  The review did not demonstrate that bisphosphonates conclusively improve clinical status (eg, by reducing pain or improving growth and functional mobility) in people with OI.

A study by Garganta et al involving 22 children with OI found that cyclic IV bisphosphonate therapy transiently reduced pain and improved functional abilities, with pain relief occurring immediately after infusion and functional improvements seen 4 weeks later. [39] Both pain and physical functioning returned to pretreatment levels by time of the next infusion.

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