tretinoin and Bone-Diseases

As both adipocytes and osteoblasts originate from the same pool of mesenchymal stem cells, increasing clinical evidence has emerged of the plasticity between the two lineages. For instance, the downregulation of osteoblast differentiation and upregulation of adipogenesis are common features of conditions such as multiple myeloma, obesity and drug-induced bone loss in diabetes mellitus. However, despite in-vitro and in-vivo observations of adipocyte transdifferentiation into osteoblasts, little is known of the underlying mechanisms.. This review summarises the current knowledge of this particular transdifferentiation process whereby the Wnt/β-catenin signalling pathway and Runx2 overexpression have been postulated to play a critical role.. Furthermore, due to the possibility of a novel therapy in the treatment of bone conditions, a number of agents with the potential to induce adipo-to-osteoblast transdifferentiation have been investigated such as all-trans retinoic acid, bone morphogenetic protein-9 and vascular endothelial growth factor.

Topics: Adipocytes; Animals; Bone Diseases; Cell Transdifferentiation; Core Binding Factor Alpha 1 Subunit; Growth Differentiation Factor 2; Humans; Osteoblasts; Tretinoin; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway

Several drugs can induce bone disorders. Steroid-induced osteoporosis is the best known of all drug-induced bone disorders. However, bone disorders have also been described in association with newer drugs (LH-RH analogs, retinoids, cyclosporine, etc.). The purpose of this revue is to familiarize radiologists with drug-induced bone disorders in order to achieve earlier diagnosis, hence, improve treatment.

Topics: Antacids; Anti-Inflammatory Agents; Anticoagulants; Anticonvulsants; Bone Diseases; Etidronic Acid; Fluorine; Heparin; Humans; Keratolytic Agents; Radiography; Steroids; Tretinoin

This is a review of the efficacy of etretinate/acitretin in the treatment of psoriasis and of the currently reported side-effects. The data indicate that retinoids bring significant improvement (if not total clearing) with frequent low-morbidity but rarely serious side-effects. The most serious side-effect of etretinate/acitretin is teratogenicity.

Topics: Abnormalities, Drug-Induced; Acitretin; Adult; Aged; Bone Diseases; Chemical and Drug Induced Liver Injury; Etretinate; Eye Diseases; Female; Humans; Lipids; Male; Middle Aged; Psoriasis; Risk Factors; Skin Diseases; Tretinoin

The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively non-toxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited.

Topics: Acne Vulgaris; Bone Diseases; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Isomerism; Isotretinoin; Keratosis; Kinetics; Psoriasis; Skin Diseases; Skin Neoplasms; Tretinoin; Triglycerides; Vitamin A

The synthetic retinoids are a new class of drugs which are highly effective in the treatment of a broad spectrum of dermatologic disease. In this report 15 patients with chronic disorders of keratinization and one patient with severe cystic acne were treated with oral isotretinoin. The degree of clinical response and duration of post-treatment remission varied with the different disorders. Acute side effects were predominantly limited to the skin and mucous membranes and were reversible after discontinuation of treatment in these patients. Acute retinoid toxicity and the potential for developing chronic toxicity are reviewed. In an attempt to facilitate the monitoring of dermatologic patients treated with oral synthetic retinoids, we present our current guidelines for the use of these agents.

Topics: Acne Vulgaris; Adolescent; Animals; Bone Diseases; Child; Child, Preschool; Etretinate; Humans; Isomerism; Isotretinoin; Joint Diseases; Keratosis; Mice; Psoriasis; Skin Diseases; Tretinoin

Topics: Adult; Antineoplastic Agents; Bone Diseases; Humans; Leukemia, Promyelocytic, Acute; Male; Pain; Pain Management; Treatment Outcome; Tretinoin

Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth.. We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age.. High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions.

Topics: Adult; Bone Diseases; Child; Female; Growth Disorders; Growth Plate; Human Growth Hormone; Humans; Lower Extremity; Medulloblastoma; Tretinoin

We prospectively analyzed skeletal changes of 16 patients who were treated with acitretin for various disorders of keratinization at doses of 10-50 mg/day (overall mean 0.4 mg/kg/day) for 7-12 months (mean 11.4 months). Skeletal changes from pretherapy findings were observed in 5 patients. In 4 of 5 patients they appeared to be linked to a preexisting degenerative pathology and could not be attributed to acitretin therapy. However, in 1 patient a spinal osseous side effect could not be excluded. No retinoid-induced extraspinal tendon or ligament calcifications were observed.

Topics: Acitretin; Adolescent; Bone and Bones; Bone Diseases; Female; Humans; Male; Middle Aged; Prospective Studies; Skin Diseases; Spinal Diseases; Tretinoin

In view of the clinical trials of retinoids as therapeutic agents for premalignant skin lesions, a radiographic study was undertaken to measure skeletal toxicities after chronic dietary administration of retinoids in mice exposed to tumor initiation and promotion. CD-1 mice were initiated with 0.15 moles of 7,12-dimethylbenz[a]anthracene and promoted twice daily with 8 nmoles of 12-0-tetradecanoylphorbol-13-acetate for 23 weeks. Diets were supplemented with 60 IU, 200 IU, or 700 IU of retinyl palmitate (RP) per g diet. After 5 weeks, the 700 IU of RP /g diet was lowered to 350 IU/g diet. Administration of these diets to mice during the 23 weeks of tumor promotion resulted in a 0-fold, 2-fold, or 10-fold increase in bone fractures, respectively. Osteoporotic bone lesions identified on radiographs rose 0-fold, 0-fold, and 10-fold at the respective doses, whereas metaphyseal flares increased 0-fold, 1.4-fold, and 3.6-fold. Bone deformities were augmented 0-fold, 1.8-fold and 2.9-fold at the respective doses. Addition of selenium (2 ppm in the drinking water) did not alter the bone toxicity of RP. 13-cis-retinoic acid (CRA) was less toxic at 700 IU/g diet than was RP at that dose, as evidenced by the death of 12 of 70 mice by the 6th week of dietary RP and no deaths in the 35 mice fed 700 IU CRA/g diet for 23 weeks. CRA at 700 IU/g diet resulted in 3/4 as many osteoporotic bones, 1/3 as many bone fractures, 4/5 as many metaphyseal flares, and a similar number of bone deformities as mice fed 700/350 IU/g diet. At the dose of 200 IU/g food, osteotoxicities were similar in the mice fed diets supplemented with RP and CRA. Thus, the light dose of CRA (700 IU/g diet) was less toxic than the high dose of, RP but at a lower dose (200 IU/g), CRA was as osteotoxic as was RP. Bone fractures in mice exposed to prolonged dietary administration of retinoids was a more sensitive index of retinoid toxicity than was body weight. We have detected osteotoxicity in mice at a total dose of CRA which was about twice the total dose used clinically.

Topics: Administration, Oral; Animals; Bone and Bones; Bone Diseases; Carcinogens; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred Strains; Osteoporosis; Retinyl Esters; Selenium; Skin Neoplasms; Tretinoin; Vitamin A

We evaluated the effects of long- and short-term isotretinoin therapy on the skeletons of patients. Eight patients who were treated with isotretinoin for disorders of keratinization received frequent radiographic evaluations for 4 to 9 years. Seven patients developed multiple hyperostoses at the spine and extremities. Hyperostoses increased in size and number over the course of therapy, although relatively few sites were symptomatic. Hyperostoses typically developed first in the spine and later in the extremities, where both bilaterally symmetric and asymmetric involvement was observed. After 5 years of therapy one patient did not develop hyperostosis. In a group of nine patients who received a relatively high dose of isotretinoin in 1982 for the treatment of acne, two patients developed tiny, asymptomatic hyperostoses. One patient had hyperostoses 1 year after isotretinoin therapy, which remained unchanged 3 years later, whereas the other patient had one hyperostosis 4 years after therapy had been stopped. Although we suspect that these hyperostoses were retinoid induced, they should not be of concern for the patient needing routine isotretinoin therapy for the treatment of cystic acne.

Topics: Acne Vulgaris; Adolescent; Adult; Bone Diseases; Child; Female; Follow-Up Studies; Humans; Ichthyosis; Isomerism; Isotretinoin; Male; Radiography; Skin Diseases; Spinal Diseases; Time Factors; Tretinoin

The roentgenographic changes noted in 13 patients, who had been treated with long-term 13-cis-retinoic acid for inherited scaling disorders, are presented. These patients were aged 13-16 years and had received this therapy for 16-87 months (mean, 58 months). The most pronounced abnormality was osteophyte formation, particularly in the cervical spine. Other changes which were noted included ossification of the anterior longitudinal and atlanto-occipital ligaments, proliferative enthesopathies, diminished bone density, premature fusion of epiphyses, and modeling abnormalities. Six of the 13 patients were asymptomatic and the osseous manifestations of this therapy were identified only by roentgenographic evaluation.

Topics: Adult; Bone Diseases; Bone Diseases, Metabolic; Child; Child, Preschool; Epiphyses; Female; Humans; Male; Middle Aged; Ossification, Heterotopic; Radiography; Skin Diseases; Spinal Osteophytosis; Time Factors; Tretinoin

An update is presented of bone changes taking place in association with oral treatment with the two most relevant synthetic retinoids, 13-cis-retinoic acid (isotretinoin; Roaccutan, Accutane) and etretinate (aromatic retinoid; Tigason, Tegison). All of the important clinical studies are reviewed, including our own results concerning etretinate-associated bone changes. While there are no more doubts about the potential bone toxicity of 13-cis-retinoic acid, the possibility of etretinate-induced bone changes probably occurring within a longer latency period cannot be conclusively assessed at present. The available clinical data concerning the potential skeletal toxicity of 13-cis-retinoic acid and etretinate should be carefully taken into consideration when determining the risk/benefit ratio, especially for long-term oral retinoid treatment.

Topics: Administration, Oral; Bone and Bones; Bone Diseases; Dermatitis; Etretinate; Humans; Isotretinoin; Retinoids; Risk; Tretinoin

During the last 10 years we treated 39 children with severe keratinization disorders with the aromatic retinoid etretinate. Six of these children were followed-up for 8-9 years. Mucocutaneous serum enzymatic and lipid side effects of etretinate were mild, transient and well tolerated. Osseous side effects were present after 4-6 years in all our 6 patients on prolonged retinoid therapy. Asymptomatic osseous neoformation and osseous reabsorption in the absence of calcium, phosphate, and alkaline phosphatase serum alterations have been observed. The growth and development curves and the sexual development of our patients (with exception of a patient with Rud's syndrome) have been normal. Osteoporosis and slender diaphysis were often present at initiation of therapy. On the basis of our findings and recent reports of the literature we suggest restricting retinoid therapy of keratinizing disorders in children to conditions severe enough to be physically, psychologically or socially incapacitating. In an attempt to reduce the risk of chronic toxicity and possibly to allow regression of initial bone alterations, intermittent therapy and combination therapy are recommended.

Topics: Adolescent; Bone Diseases; Child; Drug Administration Schedule; Drug Therapy, Combination; Etretinate; Female; Humans; Isotretinoin; Keratosis; Male; Tretinoin

Topics: Bone Diseases; Dermatologic Agents; Humans; Isotretinoin; Tretinoin

Bilateral 2.5 and 3.0 mm nasal bone osteophytes developed five weeks following the initiation of oral isotretinoin therapy (50 mg daily) for severe cystic acne vulgaris in a healthy 30-year-old white woman who had undergone uneventful rhinoplasty 12 years earlier. Histologically mature bone fragments were removed at surgery. Vitamin A and its analogs have been reported to cause hyperostosis of the vertebrae and long bones, but no known reports link them to nasal bone changes. Clinically significant nasal bone osteophytosis may be another adverse reaction to oral isotretinoin therapy.

Topics: Acne Vulgaris; Adult; Bone Diseases; Female; Humans; Isotretinoin; Nasal Bone; Rhinoplasty; Risk; Tretinoin

Sprague-Dawley rats received daily oral gavage doses of either 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone; 14, 50, 150, or 330 mg/kg) or all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration. Exposure to retinylidene dimedone did not result in any treatment-related deaths, growth depression, or histopathologic lesions, even at the highest dose, 300 mg/kg. Animals given this dosage exhibited mild anemia, equivocal evidence of bone fracture, but no increase in alkaline phosphatase activity. Retinylidene dimedone appears to be considerably less toxic than all-trans-retinoic acid.

Topics: Animals; Blood; Body Weight; Bone Diseases; Dose-Response Relationship, Drug; Female; Fractures, Bone; Male; Organ Size; Rats; Rats, Inbred Strains; Retinoids; Tretinoin

A boy with epidermolytic hyperkeratosis was treated systemically for 4 1/2 years with 13-cis-retinoic acid. At the age of 10 1/2 years, he developed pain in his right knee and radiographic evidence of partial closure of the proximal epiphysis of the right tibia. Similar radiographic changes have been described in individuals ingesting excessive amounts of vitamin A.

Topics: Bone Diseases; Child; Epiphyses; Humans; Isotretinoin; Keratosis; Male; Tibia; Tretinoin