Progress in the Prevention and Treatment of Osteoporosis in Pediatrics

Long-term effects of biphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Brumsen C, Hamdy NAT, Papapoulos SE.Medicine 1997;76:266-83. Summary: In this article the authors report their long-term experience in treating 12 young patients with severe osteoporosis secondary to juvenile osteoporosis (n = 1), juvenile arthritis (n = 1), mitochondrial myopathy (n = 1), osteogenesis imperfecta (n = 4), and idiopathic osteoporosis (n = 5). None of the subjects had previously been treated with glucorcoticoids. The subjects received either pamidronate or olpadronate, both of which are nitrogen-containing biphosphonates. The study was focused on issues of skeletal safety and efficacy. This particular class of biphosphonates was selected because unlike the first developed biphosphonate, etidronate, which has a lower therapeutic margin, the effective antiresorptive concentrations of nitrogen containing biphosphonates are considerably lower than those inducing toxicity at the bone-tissue level, thus making them more suitable for treating young patients. The subjects ranged in age from 10.7 to 17.8 years; seven were prepubertal. They were treated with daily doses of 150 mg pamidronate or 5 mg olpadronate, and the length of therapy ranged from 2 to 8 years. Longitudinal monitoring involved calcium balance studies, urinary bone resorption studies, and bone mineral density assessment using duel-energy x-ray absorptiometry (DEXA) and dual photon absorptiometry (DPA; before 1990). Six subjects also had transiliac bone biopsies performed between 2 months and 6 years after initiation of therapy. Side effects to biphosphonate therapy were minimal. One subject reported nausea that did not necessitate discontinuation of therapy. Eight subjects had a brief fever (mild), flulike symptoms, and a small decrease in lymphocyte count within the first 3 days of therapy. None of the subjects exhibited symptomatic hypocalcemia. In all cases serum electrolytes, creatinine, and liver functions were unaffected by therapy. Within 1 week of initiation of therapy there was a decline in urinary calcium and hydroxyproline excretion, indicating suppression of bone resorption. All subjects experienced increases in their bone mineral density by 0.5 to 3.0 standard deviations. Improvements were pronounced in those who were prepubertal at initiation of therapy. The prepubertal subjects also showed the radiologic changes of epiphysial and metaphysial scleroses around the knees, distal forearm, and vertebrae. Despite these changes, skeletal maturation proceeded normally. Analysis of specimens obtained bone biopsies produced normal findings with no mineralization defects or abnormalities in the lamella structure. Overall, biphosphonate therapy in these 12 subjects with severe osteoporosis was well tolerated and beneficial. Linear growth proceeded normally while treatment continued, and there was even catch-up growth in the prepubertal subjects. There was no excessive suppression of bone remodeling, assessed biochemically. In this subgroup of children with severe osteoporosis, biphosphonate therapy resulted in a positive calcium balance and marked improvement in bone mineral density. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. American College of Rheumatology Task Force.Arthritis Rheum 1996;39:1791-1801 Summary: In this article, the authors review clinical significance of glucocorticoid therapy on calcium homeostasis and pathogenesis of osteoporosis. Recommendations and guidelines for patient evaluation, treatment, and prevention of glucocorticoid-induced osteoporosis are summarized in Figure 1. Therapeutic approaches such as calcium supplements, vitamin D, thiazide diuretics, hormone replacement therapy, biphosphonates, calcitonin, anabolic steroids, and fluoride are all briefly reviewed and recommendations provided. Approaches to patients in long-term glucocorticoid therapy, with and without osteoporotic fractures, are discussed in addition to patients beginning long-term glucocorticoid treatment. Guidelines for approach in pediatric patients are also briefly discussed. The importance of nonmedicinal approaches such as the encouragement of weight-bearing exercise is also emphasized.FIG 1: Overview of recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.Comment: Brumsen et al. report a groundbreaking study of the safe and efficacious use of biphosphonates in the growing skeleton. All 12 subjects had good follow-up and experienced benefit from the biphosphonate therapy with minimal side effects. The biphosphonates are synthetic analogues of pyrophosphate, a naturally occurring substance that inhibits bone resorption by accumulating in bone and decreasing the function of the bone-resorbing cell the osteoclast. They are pharmacologically attractive because of their role as bone antiresorptive agents, thereby directly enhancing positive calcium balance and bone mineralization. Their use in osteoporosis has been associated with increases in bone mineral density and reduction in vertebral fracture and deformities (N Engl J Med 1995;333:1437-43 ). Because of a long skeletal half-life, their long-term safety in the growing skeleton has been questioned and thus reluctantly used in pediatrics. Preliminary studies on the long-term effects of biphosphonates on skeletal metabolism have shown that the biochemical markers of bone resorption return to pretreatment levels within 6 months of discontinuing therapy, whereas bone mineral density and spinal fracture index may remain unchanged up to 2 years after cessation of therapy. This suggests that whereas bone surface-bound biphosphonate is biologically active, the compound that becomes embedded during bone remodeling is biologically inert (J Clin Endocrinol Metabol 1995;80:3645-8 ). Brumsen et al. performed bone biopsies at variable times (2 months to 6 years) during therapy and found no adverse effects on the bone architecture. The magnitude of benefit increased with earlier intervention, especially if undertaken before development of puberty. The findings in this unique pediatric cohort with severe osteoporosis attest to the safe and efficacious use of biphosphonates in the growing skeleton, and the long follow-up adds strength to their findings. Patients with a variety of diseases cared for by pediatric gastroenterologists are at risk for development of osteoporosis. Chronic inflammatory bowel disease, autoimmune liver disease, and a variety of other chronic gastrointestinal disorders can be associated with the development of osteoporosis through a series of mechanisms that include negative calcium and vitamin D balance through anorexia, inadequate dietary intake, limited sun exposure, and gastrointestinal malabsorption. Low body mass and decreased physical activity further impede skeletal accretion. Inflammatory cytokines (IL-1, -6, and -11) cause increased osteoclast recruitment that results in more bone resorption, thereby promoting osteopenia and osteoporosis. Ultimately, the glucocorticoids cyclosporine and methotrexate, which are frequently used during therapy also independently cause osteoporosis. The American College of Rheumatology Task Force on Osteoporosis Guidelines lays out recommendations concerning glucocorticoids, which are the most common cause of drug-related osteoporosis. Comprehensive reviews and vast experience with glucocorticoids in the therapy of chronic rheumatologic disorders, support the strength of their recommendations. The guidelines foster a proactive approach to preventing glucocorticoid-induced osteoporosis. Implementation of the algorithms outlined ensures close monitoring and timely intervention to counteract the negative calcium balance caused by glucocorticoid therapy. Although most of the therapies apply to adult patients, these principles, appropriately extrapolated, may result in improved pediatric patient care. Proactive therapy in pediatrics is critical because peak bone mass is achieved during the first two decades of life. Therefore, exposure to protective or detrimental factors during growth may produce generalized and specific effects that could influence bone mass and subsequent fracture and osteoporosis risk. To date, the standard recommendations for prevention of osteoporosis in pediatrics involve ensuring adequate dietary calcium intake. This is supported by studies showing that calcium intakes above the recommended dietary allowance resulted in better bone mineralization, with greater benefits experienced in those with intervention before onset of puberty (N Engl J Med 1992;327:82-7 ). Children with risk factors for osteoporosis may be further evaluated for vitamin D status, and weight-bearing physical activity is encouraged. The findings of Brumsen et al. also corroborate the benefits of timely intervention of antiosteoporosis therapy initiated before onset of puberty. In summary, children with chronic gastrointestinal disease are known to be at increased risk for osteopenia and osteoporosis. This risk is further exacerbated by the medications, in particular glucocorticoids, that are often used during therapy. The task force's recommendations provide excellent guidelines for the monitoring, prevention, and treatment of glucocorticoid-induced osteoporosis, and an adaptation to our patient population should be considered. Current proven antiosteoporosis therapies remain limited in pediatrics, making the search for newer therapies an ongoing venture. Biphosphonates are antiresorptive agents that result in a positive calcium balance and increased bone mineralization in steroid- and nonsteroid-induced osteoporosis (N Engl J Med 1995;333:1437-43 ; Am J Med 1995;99:235-42 ); however, data regarding safety in the growing skeleton must precede their use in pediatrics. Brumsen et al. have shown encouraging data in this regard. Comprehensive monitoring of patients treated with glucocorticoids and new therapies such as biphosphonates are an important step in the prevention and treatment of osteoporosis during the critical periods of skeletal accretion in childhood and adolescence. These articles are just the a beginning in helping pediatricians become aware of osteoporosis as a greatly underdiagnosed and undertreated problem. Timothy A. S. Sentongo Barbara Haber Division of Gastroenterology and Nutrition; The Children's Hospital of Philadelphia; 34th and Civic Center Boulevard; Philadelphia, PA 19104, U.S.A.