Definition
This is a congenital metabolic bone disorder, also known as “brittle bone disease”.
It is the commonest of the congenital disorders involving bones and muscles and is caused by a defect in the synthesis of collagen type I, the principal component of bone matrix. Osteogenesis Imperfecta (OI) occurs in about 1 of 20,000 live births. In the USA there are about 15,000 patients with OI. The clinical picture var- ies according to the severity of disease, which ranges from lethal to pronounced skel- etal anomalies in childhood to an apparently typical picture of osteoporosis in later life. Due to the variable clinical manifestations, OI is often missed altogether, or the diagnosis is delayed, or the condition is even misdiagnosed as something else.
Four types are distinguished:
▶ Type I Mild with blue sclerae
▶ Type II Perinatal, lethal
▶ Type III Progressive, deforming
▶ Type IV Mitigated, without blue sclerae
Inspection of the patient’s eyes is an essential part of the physical examination.
Pathophysiology
OI is caused by various mutations of the genes for collagen type I which result in abnormalities of the helical structure of collagen and these, in turn, are re- sponsible for the development of abnormal bone, the absence of lamellae and the increased sensitivity to dissolution by collagenases. Other organs which contain collagen are also effected. These include:
▶ Eyes: Thin blue sclerae liable to rupture (Fig. 10.1)
▶ Teeth: Appear somewhat transparent and discolored (brownish), liable to loose- ning
118 Chapter 10 Osteogenesis Imperfecta (OI)
▶ Ears: Deafness (bi or uni-lateral) due to damage to the bones (stapes) of the middle ear
▶ Heart and vessels: Anomalies of cardiac valves and aorta
▶ Kidney: Stones and hypercalcemia
▶ Hyperplastic callous formation after injuries or surgery
Diagnosis
Any young patients with osteoporosis of unclear etiology and/or with multiple, mainly peripheral fractures are suspect for OI and should be investigated. The investigation should include:
▶ Family history
▶ Physical examination
▶ Test of hearing
▶ Examination of eyes and teeth
▶ Cardiac examination
▶ Results of imaging techniques: skeletal deformities, evidence of previous frac- tures and deformities
However, today the diagnosis is established much earlier, and even very young patients – infants – have been treated successfully.
Treatment Strategies
Previous treatments with fluoride or by means of bone marrow transplantation were not successful. Today the treatment of choice is the early administration of
Fig. 10.1 Blue sclerae in patient with osteogenesis imperfecta
bisphosphonates orally or i.v. in patients with severe OI. Moreover, bisphospho- nates have been given to infants and young children to prevent consequences of OI. Therefore it is worth-while emphasizing that early and effective treatment is possible at any age – it could even spare the patient a life-time in a wheel-chair!
Bisphosphonates
The results of long-term clinical trials of aminobisphosphonates in children with OI and young adults with juvenile osteoporosis have now been published and their efficacy confirmed. The rationale for the therapy is simple: the collagen syn- thesised in OI is qualitatively inferior which stimulates the osteoclasts to resorb the bone produced and this resorption is inhibited by bisphosphonates. Side ef- fects of bisphosphonates, such as disturbances of growth and of mineralisation were not observed. Moreover, bone biopsies have demonstrated no deterioration of bone structure, even after years of therapy with bisphosphonates. In one study, 50 OI patients were treated with ibandronate or pamidronate for a period of three years, and the following effects were demonstrated:
▶ Increase in bone density
▶ Improvement of bone quality
▶ Fewer clinical symptoms and complaints
Fig. 10.2a,b Qualitative anomalies of bone structure in osteogenesis imperfecta (OI). a Lamel- lar bone in a healthy subject for comparison. b Almost complete loss of lamellae in patients with OI, indicating disruption of collagen metabolism
120 Chapter 10 Osteogenesis Imperfecta (OI)
▶ Dramatic reduction in fracture rate
▶ In another study, four years of cyclic pamidronate therapy i.v. lead to a signifi- cant height gain in moderately to severely effected OI patients
This last effect cannot be due entirely to the increase in bone density. Improvement of bone quality probably also played a role: bone examined by electron microscopy showed a distinct lamellar structure in contrast to that of the previously disorgan- ised tissue (Fig. 10.2). Moreover, in adults treated with risedronate, an increase in radial width was observed, which supports the hypothesis that bisphosphonate therapy induces structural changes not detectable by BMD measurements, and these changes substantially decrease the fracture risk in OI.
The following protocols are recommended:
▶ Ibandronate (Bonviva®) 3 mg infusion (15 min) every 3 months
▶ Pamidronate (Aredia®) 30–60 mg infusion (30–60 min) every 3 months
▶ Zoledronate (Aclasta®) 5 mg infusion (15 min) annually
▶ Alendronate (Fosavance®) 70 mg orally weekly
Results of long-term studies of children treated with aminobisphosphonates, both for OI and for juvenile osteoporosis, have now been published. Most importantly these studies have demonstrated that alendronate therapy is safe, effective and has improved the quality of life of children with OI. In addition, oral alendronate was also convenient especially for children of school age. Side effects such as clinically relevant disturbances of growth or of mineralisation were not observed. Bone bi- opsies demonstrated a normal bone structure even after years of therapy. These studies clearly showed that treatment of children is possible and effective but therapeutic decisions must be taken together with the parents and an experienced pediatrician and approved by the ethics committee of the hospital. Consent must be obtained and documented.
Osteopenia of Prematurity
Since it has now been demonstrated that bisphosphonates can be given to young children even infants with OI, the question arises could they also be used for the osteopenia of prematurity? The survival rate of premature infants has been steadily increasing so that other problems are also steadily emerging including that of osteopenia which has been reported to be as high as 30% of infants born be- fore 28 weeks of gestation. This poses a challenge because prevention of continued bone loss is crucial in order to enable normal growth and attainment of peak bone
mass. Can bisphosphonates do the job? Time will tell. In addition other studies have shown that passive range of motion of the extremities of premature infants results in a significant increase in bone formation markers and bone density and are im- portant in the prevention and treatment of osteopenia of prematurity.
