Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review (Jayasena A, et al.)

Glucocorticoids are widely used in pediatric practice, and long-term systemic GC therapy is associated with many side effects, including low bone mineral density (BMD) and fragility fractures. To that end, Sri Lankan researchers conducted a systematic review with the aim to critically evaluate the treatment options used in the management of bone loss associated with glucocorticoid use among children.

Performing a systematic search using PubMed, Cochrane clinical trial registry, Clinicaltiral.gov, and Ovid databases (1 March, 2013), the search resulted in 34 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by two authors. Four studies have compared the effectiveness of bisphosphonates in the treatment of GC-induced low bone mineral density (BMD) in children. Remaining studies were on menatretenone (vitamin K2 as MK-4) + alfacacidol versus alfacalcidol alone, calcium + vitamin D versus placebo and alfacalcidol versus menatetrenone.

According to the researchers, “In the four studies, bisphosphonates have shown the ability either to improve BMD or prevent bone loss associated with GC use in children. However, alendronate either in oral or intravenous routes and oral pamidronate were the only bisphosphonates that have been studied in children.

“Several studies have reported the efficacy of vitamin K2/menatetrenone (MK-4) in the treatment of GIO (glucocorticoid-induced osteoporosis.), adult form, in Japan. Vitamin K2/menatetrenone along with vitamin D3 appear to have a protective effect on lumbar BMD in GIO,” the researchers wrote. “Vitamin K2 (menatetrenone) combined with alfacalcidol has also preserved BMD in children on long-term GC therapy. Furthermore, vitamin K2 is shown to have a preventive effect on occurrence of new fractures in osteoporosis. Thus the findings of Inoue et al. are comparable with the existing data in the adult population, although latest evidence from Rianthavorn et al. show that alfacalcidol can prevent further bone loss to a greater extent than menatetrenone.”

While the researchers noted that menatetrenone lacks approval for the treatment of osteoporosis in any part of the world and also is not included in any management guidelines related to osteoporosis, Dr. Katarzyna Maresz, president of the International Science and Health Foundation, commented that this review lacks studies using vitamin K2 as menaquinone-7 (MK-7) as opposed to menatetrenone (MK-4).

“The two most commonly commercialized forms of Vitamin K2 are MK-4 and MK-7. Due to its side chain, the MK-7 version of Vitamin K2 has a much longer half-life in the body than MK-4, allowing it greater access to the extrahepatic tissues,” said Dr. Maresz. “The serum half-life of MK-4 has been shown to be just a few hours compared to a 3+ day half-life for MK-7. So although they have the same molecular mechanism of action, MK-7 is more bioavailable than MK-4.

 

Further, Dr. Maresz noted that due to MK-4’s short half life and poor bioavailability, the MK-4 form requires multiple doses per day at milligram levels (vs MK-7’s microgram levels) for measurable efficacy.

“In a 2007 3-year, placebo-controlled, double-blind trial, healthy postmenopausal women were given 45 mg/day of MK-4 or a placebo. While MK-4 had a beneficial effect on bone as compared to placebo, this was a daily milligram dose that is much higher than the nutritional microgram dose (180 mcg/day) proven effective in the Knapen et al. 2013 3-year human clinical trial published a few years later in the same journal.”

Reference: Jayasena A, Atapattu N, Lekamwasam S. Treatment of glucocorticoid-induced low bone mineral density in children: a systematic review. Int J Reum Dis.  2015 Mar;18(3):287-93.

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