Retinoid-induced skeletal hyperostosis in disorders of keratinization.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

Cortical hyperostosis as a side-effect of prolonged use of prostaglandins.

Cortical hyperostosis is a very uncommon side-effect of prolonged prostaglandin therapy with distinctive radiological signs that may be accompanied by painful swelling of the limbs and responds rapidly to withdrawal of therapy.

Non-traumatic hypertrophic callus of the fibula mimicking osteosarcoma in osteogenesis imperfecta type V: a case report.

We report a case of hyperplastic callus mimicking osteosarcoma in the fibula of a patient with osteogenesis imperfecta type V. Among the various imaging modalities, computed tomography was the most useful in distinguishing this rare process from a malignant entity. In addition, simple radiographs demonstrated the presence of characteristic "zebra lines", a manifestation of cyclic bisphosphonate therapy during childhood.

Improvement of nonbullous congenital ichthyosiform erythroderma following functional endoscopic sinus surgery.

We report the case of a child with congenital nonbullous ichthyosiform erythroderma on long-term isotretinoin who developed progressively worsening ichthyosis along with recurrent bouts of sinusitis. Endoscopic sinus surgery revealed osteophytes, most likely an isotretinoin-related adverse event, and post operatively the patient's sinus disease and skin disease both dramatically improved. This case represents the first report, to our knowledge, of ichthyosis improving after endoscopic sinus surgery.

Cortical hyperostosis: a complication of prolonged prostaglandin infusion in infants awaiting cardiac transplantation.

BACKGROUND: Infants awaiting heart transplantation for congenital heart disease frequently require prostaglandin E1 (PGE1) infusion for prolonged periods. As a result, complications of prolonged PGE1 infusion, such as cortical hyperostosis, are being encountered more commonly. OBJECTIVE: To determine the incidence and severity of cortical hyperostosis in newborns requiring prolonged PGE1 infusion. METHODS: Chest radiographs of 86 infants receiving PGE1 infusion awaiting heart transplantation were reviewed. The chest radiographs were graded for the severity of cortical hyperostosis (no bony changes, minimal hyperostosis, or severe hyperostosis). Duration of PGE1 infusion, total PGE1 dose, and highest alkaline phosphatase were recorded for each patient. Infants were arbitrarily divided into three groups according to the duration of PGE1 infusion (< 30 days, 30 to 60 days, > 60 days). RESULTS: Fifty-three of the 86 infants (62%) had radiologic evidence of cortical hyperostosis. Forty-two of 80 infants (53%) had elevated alkaline phosphatase. The percentage of infants with hyperostosis increased with increasing duration of PGE1 infusion (42% at < 30 days; 87% at 30 to 60 days; 100% at > 60 days). The incidence and severity of cortical hyperostosis were related (by Kruskal-Wallis) to the duration of PGE1 infusion (P < .0001) and the total dose of PGE1 received (P < .0001). The highest alkaline phosphatase levels were observed in infants with the most severe grades of hyperostosis (P < .0001). The percentage of infants with elevated alkaline phosphatase increased with greater severity of hyperostosis (26% of infants with no bony changes, 59% with minimal changes, and 85% with severe changes). Two infants had symptomatic bone tenderness or swelling mimicking osteomyelitis. CONCLUSION: It is concluded that cortical hyperostosis is a frequent, often asymptomatic, side effect of prolonged PGE1 infusion that should be evaluated in any infant on long-term PGE1 therapy. When symptoms occur in infants awaiting transplantation, osteomyelitis must be excluded rapidly to avoid an unnecessary delay in transplantation.

Enthesopathy of the patellar tendon insertion associated with isotretinoin therapy.

A 99mTc-MDP bone scan performed on a 34-yr-old female for suspected osteomyelitis of the proximal tibia revealed focally increased activity in both tibial tuberosities due to enthesopathies secondary to chronic isotretinoin therapy. Physicians should be aware that isotretinoin therapy can cause abnormal bone scans and not mistake these abnormalities for other diseases such as osteomyelitis. Second, bone scans may be helpful in diagnosing and following isotretinoin bone toxicity.

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

Cortical hyperostosis in an infant on prolonged prostaglandin infusion: case report and literature review.

The common side effects associated with the use of prostaglandins in newborn infants include apnoea, hyperthermia, diarrhoea, skin flushing and oedema. Periosteal reaction or cortical thickening of the bones, also known as cortical hyperostosis, is associated with a prolonged use of prostaglandins. This is a radiological diagnosis; therefore, its occurrence is most likely underestimated. We describe an infant who developed cortical hyperostosis simulating osteomyelitis with elevated alkaline phosphatase. The radiologic changes were initially attributed to congenital syphilis. This occurred after a prolonged infusion of prostaglandin E(1) for a cyanotic congenital heart disease.

Cortical hyperostosis: a complication of prostaglandin E1 treatment in congenital heart disease.

Prostaglandin E1 (PGE1) is an essential drug for infants with ductal-dependent congenital heart disease. Cortical hyperostosis of the long bones is one of the complications during and after PGE1 therapy and should be considered in the differential diagnosis of periostitis in the infant.

Rat-specific decreases in platelet count caused by a humanized monoclonal antibody against sclerostin.

LY2541546 is a humanized monoclonal antibody (IgG(4)) that has been optimized for neutralizing activity against sclerostin. In 5-week and 6-month nonclinical safety studies in rats, LY2541546 caused dose-dependent reversible decreases in platelet counts accompanied by accelerated platelet production, increased megakaryocytes, and altered megakaryocyte morphology. These treatment-related effects resulted in altered primary hemostasis as manifested by prolonged bleeding after phlebotomy or incidental toenail break. In some cases, the defects in hemostasis were sufficient to result in death of the affected rats. There was no evidence in rats of general bone marrow suppression or processes (e.g., disseminated intravascular coagulopathy) that may result in thrombocytopenia. Cynomolgus monkeys given LY2541546 for 5 weeks or 9 months had no changes in platelet count or megakaryocytes. In vitro cross-reactivity studies in rats, cynomolgus monkeys, and humans revealed LY2541546-bound rat but not cynomolgus monkey or human platelets and megakaryocytes. These data taken together demonstrated that the platelet and megakaryocyte effects in rats had a species-specific pathogenesis which likely involved LY2541546 binding of a rat-specific antigen on the surface of platelets and megakaryocytes resulting in the increased clearance of platelets and megakaryocyte hyperplasia. The species-specific nature of these reversible toxicological findings combined with the ease of clinical monitoring using standard hematology enabled the safe initiation of clinical studies in human volunteers.

Spontaneously occurring alimentary osteofluorosis associated with proliferative gastroduodenopathy in rabbits.

Growing rabbits from two rabbitries, fed with commercial concentrates and hay, developed painful thickenings of the extremities. Four rabbits from each farm were clinically examined and necropsied. All animals showed multiple moderate to severe osseous proliferations of extremities and mandibles and a mild to severe proliferative gastroduodenopathy. Histologically, periosteal and endosteal hyperostosis and a mild to severe proliferation of the gastric and duodenal mucosa were noted. Bone analyses revealed 12,700 and 15,000 microg fluoride per gram of bone ash in affected rabbits, compared with 550 microg fluoride in a control animal. A highly elevated fluoride content was found in concentrates. Vitamin A levels were moderately increased only in one concentrate, and copper levels were normal. Results indicate that alimentary fluoride intoxication caused prominent bony proliferations in the examined rabbits. Whether the proliferative gastroduodenopathy is related to the elevated fluoride intake or represents an incidentally occurring secondary disease remains to be determined.

Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years' experience on 23 patients.

BACKGROUND: Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children. OBJECTIVES: The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago. METHODS: Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes. RESULTS: Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate. CONCLUSIONS: This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids.

Prostaglandin E1-induced hyperostosis: clinicopathologic correlations and possible pathogenetic mechanisms.

Prostaglandin E1 (PGE1) causes skeletal hypertrophy, a phenomenon noted when it is administered for several weeks to maintain ductus arteriosus patency in neonates with congenital heart disease. This effect, a dose-dependent and reversible hyperostosis, was described radiologically as bone within bone, but skeletal histopathology was not studied. We compared postmortem gross, radiological, and histological bone findings for untreated controls and term gestation infants after 4, 27, and 56 days of continuous 0.1-0.2 microgram/kg/min PGE1. Bone was not significantly different from controls after 4 days of PGE1. Radiographs were negative after 27 days, but femoral cortex showed early periosteal osteoblast proliferation. At 56 days of PGE1, there was severe, radiologically apparent neocortex formation in tubular, rib, and scapular bones. Corresponding sections of femoral shaft revealed distinctive histopathology with thickened periosteum and fibrocartilage-like tissue covering an exuberant neocortex of closely aligned, gracile, woven bone trabeculae. Paratrabecular stroma contained ectatic capillaries orthogonally oriented to the periosteum, suggesting that a vascular reaction to PGE1 is important in the observed effect. The native cortex was partially resorbed; because it is stress shielded by the neocortex and no inflammation was present, this was interpreted as a secondary effect. We conclude that PGE1-associated paracortical bone hypertrophy is distinct from inflammatory processes and that its early stages may not be apparent radiologically. Moreover, the time course of PGE1-induced osteoblast proliferation and mineralization suggests that experimental use for 4-8 weeks may benefit conditions such as ununited fractures.