Radiographic image of chronic bone changes and angular deformities in osteogenesis imperfecta. In this image, note healing fracture of the proximal shaft of the right femur, with two medullary pins. Both limbs demonstrate a degree of varus angulation. An age indeterminate partially remodeled fracture of the left femur is also evident, with a minor degree of residual deformity. Both legs are gracile in shape with bowing most marked of the right tibia, but seen in all bones (Source: radiopaedia.org/cases/osteogenesis-imperfecta-2. Accessed 27 Jan 2016)
Classification of OI and key features
Bones fracture easily
Blue-gray discoloration of the sclera
Defective type 1 collagen leads to discoloration of sclera
Poor muscle tone and loose joints
Slight spinal curvature
Slight protrusion of the eyes
Early hearing loss in some children
Severe; often fatal within perinatal period
Respiratory failure and other severe respiratory problems due to underdeveloped lungs
Severe bone deformity and small stature
Progressive; moderate in severity
Considered progressive and deforming
Bones fracture easily
Bone deformity (often severe)
Poor muscle tone and loose joints
Blue-gray discoloration of the sclera
Possible early hearing loss
Short stature and spinal curvature
Possible respiratory problems
Moderate in severity; variable
Bones fracture easily (prepuberty)
Short stature and spinal curvature
Barrel-shaped rib cage
Mild to moderate bone deformities
Early loss of hearing
Moderate in severity
Clinically similar to type 4
Characteristic histologic findings (e.g., mesh-like bone)
Calcification of interosseous membrane
Hyperplasic callus at site of fractures
Radial head dislocation
Mixed hearing loss
Long bone bowing
Moderate in severity
Clinically similar to type 4
Characteristic histologic findings (e.g., fish-scale bone)
Mineralization defect seen in bone
Lethal in all identified cases with a complete absence of the cartilage associated protein
Some cases are clinically similar to type 4; other cases are clinically similar to type 2
Shortened long bones (e.g., humerus, femur)
Short stature and coxa vara
Severe to lethal; associated with mutations in the LEPRE1 gene and leprecan protein
Clinically similar to types 2 or 3 except that sclera remains white
Severe growth deficiency
Extremely under-mineralization of the skeleton
One overriding concern for persons with OI is bone density. During their growth period, children are prone to bone loss, resulting in impaired bone development and the failure to reach peak bone mass at any age. Consequently, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and related organizations continuously emphasize that osteoporosis is an almost universal consequence of OI. The goal of osteoporosis management in the context of OI is twofold: to increase bone density at every age and to minimize age-related bone loss . Additional age-related osteoporosis is compounded by the preexisting effects of OI, and by middle age, fracture rates tend to increase.
Bone density measurements, including both dual-energy x-ray absorptiometry (DXA) and quantitative computer tomography (QCT) are essential in managing OI in both children and adults. For children, they are critical in assessing skeletal development and the likelihood of fracture occurrence while also providing a measure for studying the effects of different forms of therapy. They are also recommended for adults to establish a baseline for determining whether bone density changes over time or as a result of treatment. In individuals with OI, bone density measurements may be affected by such deformities as curvature of the spine or by the placement of metal rods.
Management of Type 1 OI and Osteoporosis in Children
Nonpharmacologic Treatment: Therapy and Surgical Intervention
Given the number of confounding conditions evident in OI, a multidisciplinary approach involving pediatricians, surgeons, physical therapists, nutritionists, and even parents and educators is the most effective way to manage the disease in children and adults . Fracture management and protection are the mainstay of OI treatment. To prevent immobility-induced bone loss following a fracture, casting is recommended for only the short term, to be replaced by splints and braces that can be removed to permit appropriate physical therapy. The need to avoid twisting, jolting, and jarring movements is of paramount importance, underlying the value of water therapy and swimming which offer a gravity-free environment to reduce fracture risk. Coupled with water activities, hip extension and hip abduction exercises, walking, dancing, bicycling, and weight lifting, if permitted, can help promote maximum bone density and decrease muscle atrophy [14, 15].
In children with OI, physical activity and an appropriate diet are essential to prevent obesity, which results in less movement and places added stress on bones. Adequate amounts of calcium to help prevent bone loss, vitamin D to promote calcium absorption, and vitamin C to ensure healthy connective tissues are also recommended. Smoking and excess alcohol consumption that can result in falls and fractures should also be avoided although primarily relevant in older teenagers.
Surgical interventions are generally unnecessary in type 1 OI. However, if severe bone deformities or serious fractures are present, surgeons are able to insert metal rods into the long bones of the legs to reduce fracture risk. Using the Fassier-Duval Telescopic Intramedullary System designed for OI patients who are still growing, a rod is attached on the far end of each growth plate and telescopes as the bone grows, overcoming the fracture risk posed by older rods with a fixed length .
In recent years, research studies on the treatment of osteogenesis imperfecta and osteoporosis have focused increasingly on drug therapy and particularly on the role of bisphosphonates as antiresorptive medicines that reduce the rate at which osteoclasts remove the bone and thus prevent the loss of bone mass. Clinical trials on the effectiveness of bisphosphonates have focused on children with severe OI, but some have been expanded to encompass those who are mildly or moderately affected. Studies incorporating patients with type 1 OI indicate that although bisphosphonate use is not recommended for the group as a whole, it may have individualized benefits for patients with repeated fractures and low bone density findings. For example, in a study of intravenous pamidronate (the most commonly used bisphosphonates for OI), Zacharin and Kanumakaia reported improved bone quality, increased mobility, and reduced fracture occurrence in children with less severe OI .
Other trials involving a range of OI types and other bisphosphonates such as IV ZA and oral alendronate show promising results [18, 19]. Although no bisphosphonate is FDA approved as OI therapy for children, “off-label” bisphosphonates are increasingly becoming the standard of care in children with moderate to severe forms of OI, reflecting demonstrated positive effects ranging from increased BMD and enhanced vertebral height to pain relief and greater muscular strength and mobility . However, concerns have been raised about both the efficacy of bisphosphonates in reducing fracture risk and the duration of their use in children. Citing the results of several recent studies [21–23], Brizola and Shapiro warn that despite positive results from individual studies, an overall analysis of numerous trials reveals no clear consensus on whether bisphosphonates consistently decrease the incidence of fractures in children or adults with OI, nor is there evidence to address the concern that continued long duration treatment may adversely affect bone .
Within the last few years, a series of new investigations have been published, further elucidating the effect of pharmacologic interventions in OI. In a systematic analysis of the clinical, biochemical, and radiological outcomes of ten studies involving only children, Rijks et al. found that six trials indicated a significant reduction in relative fracture risk as a result of bisphosphonate therapy, with the optimal duration of such therapy still unclear . In an effort to assess long-term treatment outcomes with bisphosphonates (pamidronate/ZA), Palomo et al. reported that 37 children who began bisphosphonate therapy (pamidronate/ZA) before age five and were close to or at final height at the time of the study had increased Z-score for LS BMD and taller stature but still sustained frequent fractures of long bones and developed progressive scoliosis, underlining the role of bisphosphonates as an adjunct treatment .
Beyond bisphosphonates, the positive effects of other medications on OI, including combination therapies such as recombinant growth hormone plus bisphosphonates, have been examined. Moreover, the first prospective clinical trial of denosumab in OI children has demonstrated a mean relative change in LS BMD of +19 % and bone resorption suppression for a duration of 10–12 weeks, indicating that denosumab should be safe in a 1-year treatment regimen with calcium and vitamin D supplementation. The effect of denosumab on fracture occurrence and the optimal duration of treatment are yet to be assessed . Greater understanding of the mechanisms underlying OI holds promise of developing novel molecular therapies through infusion of mesenchymal stem cells .
Management of Osteogenesis Imperfecta and Osteoporosis in Adults
Beginning in childhood, patients with OI should be taught to assume responsibility for themselves and to achieve as much independence as possible, given the severity level of the disease. Although generalized transition programs exist, they cannot encompass all the variable conditions associated with OI, underlying the need for approaches tailored to the medical condition and preferences of individual adults . Critical to the transition is the continuity of medical care between pediatric and adult physicians and between physicians with limited knowledge of OI care and those with greater experience .
Clinicians must be aware of the confluence of conditions directly associated with OI and those affecting otherwise healthy aging adults, recognizing that, to a certain extent, the treatment for both may be the same. A decline in bone density can be related to immobilization from casts and lack of weight-bearing exercise as well as to age-related changes in the skeleton and hormonal system; however, symptoms of bone loss may appear at an earlier age than seen in people without OI. Periodic bone densitometry tests are recommended to identify osteoporosis, determine fracture risk, and monitor response to prescribed treatment. A healthy lifestyle, appropriate weight, adequate calcium and vitamin D through foods or supplements, smoking abstinence, limited alcohol use, and a safe exercise program, particularly aquatic therapy, will benefit patients with most types of OI. Those with type 1 may also be able to engage in noncontact sports that do not involve extensive twisting. Because they contribute significantly to bone loss, corticosteroids should be avoided .
Although fracture risk is known to decline following puberty, OI is a connective tissue disease, and adult patients with mild or moderate OI, particularly those with excessive joint flexibility, are likely to experience more soft tissue injuries as they age . Impaired connective tissue can, in turn, lead to fractures as well as tendon, ligament, and muscle injuries and severe pain.
Bisphosphonate treatment has been studied in OI adults but to a more limited extent than in children and, thus far, with fewer positive results regarding fractures. Two studies of adult OI considered in a Cochrane review  revealed conflicting results. Although Adami et al.  reported a 14 % reduction in fracture incidence following treatment with IV pamidronate, further analysis of a subgroup of Adami’s subjects who had incurred at least one fracture  demonstrated no difference in fractures between these patients and controls. In a study involving alendronate, Chevral et al.  indicated no difference in vertebral or peripheral fracture rates. Both trials showed a significant increase in bone density.
Since 2010, additional studies of bisphosphonate treatment of OI in adults by Pavon de Paz et al. , Shapiro et al. , and Bradbury et al.  all reported an increase in BMD, but the results for fracture rate reduction were inconclusive. Shapiro indicated that while bisphosphonates did not decrease fracture rate in type 1 OI, IV pamidronate did lead to fracture reduction in more severe forms of the disease; Bradbury’s meta-analysis found no significant difference in fracture incidence in OI patients with oral bisphosphonates. At this point, insufficient evidence in support of the efficacy of bisphosphonates in reducing fracture rates does not justify a recommendation for general use, particularly over the long term when antiresorptive treatment has been associated with increased risk of atypical femoral fractures in OI patients . Since there is such growing controversy in this area, expect to see more individualized approaches to treatment of patients with OI in terms of initiation of bisphosphonates.
The first trial examining the effect of the anabolic agent, teriparatide , on adult OI has produced positive results for type 1 in terms of increased hip and spine aBMD, vertebral vBMD, and markers of bone formation; efficacy was attenuated in more severe types 3 and 4. Larger trials are needed to evaluate teriparatide’s ability to reduce bone fractures in OI as well as to compare its effectiveness with that of bisphosphonates and other anabolic agents and when used in combination with other antiresorptive treatments. Several new therapies requiring further investigations have the potential to benefit patients with OI; they include cell-based therapies including bone marrow transplantation and gene therapy that focus on silencing, decreasing, or replacing the allele carrying the causative variant, effectively transforming a severe type of OI into a milder form of the disease [38, 39].
As adults age, the effects of adult OI are likely to be compounded by age-related osteoporosis. For the present, patients with OI, particularly type 1 combined with osteoporosis, must rely on the most promising pharmacologic treatments as well as nonpharmacologic interventions including good nutrition, adequate amounts of calcium and vitamin D, physical therapy to strengthen muscles, and occupational therapy to address educational, work, and ADL needs.
Juvenile Idiopathic Arthritis
Once classified as juvenile rheumatoid arthritis in the United States and as juvenile chronic arthritis in Europe, the term “juvenile idiopathic arthritis” (JIA) has now been adopted as an international designation for a group of autoimmune diseases that result in chronic joint inflammation and stiffness, lasting more than six weeks in children aged 16 and younger. Some patients experience the disease only in childhood and adolescence; for others, JIA persists into adulthood.
Juvenile Idiopathic Arthritis in Children
Causes and Types
The underlying cause of JIA is thought to be both genetic and environmental. Research indicates that the genetic composition of a patient results in a tendency to develop the disease, which is then actually triggered by environmental factors such as early-age infections/viruses and possibly breastfeeding or maternal smoking . A recent study of 153 children with JIA proposed another possible causal factor: exposure to antibiotics during childhood. Compared to children with no exposure to antibiotics, the ratio for developing JIA was 3:1 for those with one to two courses of antibiotics and 3:8 for those with three to five courses .
Divided into seven subgroups on the basis of the number of joints involved, the symptoms, and the presence of distinct antibodies in the blood, JIA will be separated into three broader categories for consideration in this chapter [42–44]:
Oligoaricular (Pauciarticular) JIA—Affecting half of JIA children with girls at greater risk than boys, it involves four or fewer joints in the 6-month onset period; if five or more joints become involved after the first six months, patients are said to have an “extended” form of the disease which develops in up to half of subjects and may persist into adulthood. Symptoms include large joint involvement of the lower extremities, particularly the knees, with little pain and little difficulty in functioning. About 70 % of patients are antinuclear antibody (ANA) positive, making them prone to eye diseases such as iritis and necessitating regular ophthalmologic examinations to prevent serious vision loss. This form of the diseases carries the best prognosis.
Polyarticular JIA—Occurring in 30 % of children with JIA, it affects five or more large and small joints, particularly those in the hands and feet, and is symmetrical, affecting the same joints on both sides of the body. Morning stiffness, joint swelling, and limited range of motion in the affected joints are among the symptoms. Complications include joint space narrowing, bone erosions, flexion contractures, and some growth disturbances. Because patients with this type of JIA generally have a positive blood test for proteins called rheumatoid factors, it may represent an earlier iteration of rheumatoid arthritis.
Systemic JIA (Still’s disease)—Affecting the whole body and occurring in 10–15 % of those with JIA, it is characterized by two weeks of spiking fevers, a salmon-colored rash, and inflammation of internal organs; joint swelling in some patients may not appear until months later. Anemia, leukocytosis, thrombocytosis, and elevated liver enzymes are associated with systemic JIA as are such complications as osteoporosis, infection from immunosuppressive therapy, growth disturbances, and cardiac disease.
No single test can diagnose JIA. The first step in the process is a thorough physical examination and a detailed medical history. Laboratory tests include a complete blood count to detect abnormalities in red blood cells, white blood cells, and platelets; liver function tests and ANA tests to detect autoimmunity and risk of eye disease; bone scans; and the erythrocyte sedimentation rate to measure how rapidly red blood cells settle to the bottom of a test tube, indicating inflammatory conditions within the body . A differential diagnosis to rule out conditions with symptoms similar to those in JIA incorporates infections, malignancy, collagen vascular diseases, Lyme disease in oligoarticular JIA, and acute rheumatic fever in systematic JIA [44, 46]. Early diagnosis of JIA is imperative to prevent irretrievable damage to joints and organs, identify potential complications, reduce the risk of impaired vision and possible blindness and develop an effective treatment plan.
Treatment of JIA involves a combination of medications, physical therapy, regular exercise, and nutrition.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, once the mainstay of JIA therapy, are now used largely as bridge or adjunctive therapies . NSAIDs (aspirin, ibuprofen, naproxen, COX-2 inhibitors) reduce pain and inflammation, but their serious side effects including stomach, liver, kidney, and heart problems as well as high blood pressure and anemia outweigh their benefits, especially in comparison to biologic agents. Corticosteroids (hydrocortisone, prednisone) have been prescribed to treat serious symptoms such as inflammation of the lining of the heart, but adverse effects such as growth disturbances, weakened bones, osteoporosis, and increased susceptibility to infection inhibit their long-term use .
Disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, slow the progression of JIA and prevent the disorder from worsening but may take as much as 3–6 months to take effect. Administered in small doses, methotrexate does not incur dangerous side effects but can lead to anemia, immune suppression, low blood count, and kidney and liver problems, requiring regular physician monitoring. Nonetheless, as Stoll observes, its long track record of safety and efficacy justifies its standing as the “gold standard” therapy for children with JIA .
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