Dear Editor,
We thank Drs. Xie and Ye [1] for their interest in our paper [2] and address their main comments below.
Firstly, we were careful to acknowledge the contrasting findings of other published studies, both in vitro and in vivo. We do not know of any evidence to support the assertion of Drs. Xie and Ye that “Sr2+ concentrations in biological microenvironment(s) play essential roles in bone formation”.
Secondly, Drs. Xie and Ye are concerned that we did not study sufficiently high concentrations of Sr2+ in our osteoblast experiments. We chose Sr2+ concentrations that spanned the maximum circulating Sr2+ level (about 0.1 mM), measured in patients treated with 2 g/day strontium ranelate [3]. We emphasise that this concentration of Sr2+ was already sufficient to cause near-total inhibition of bone mineralisation in our cell cultures, and thus, no additional effect was observed at the highest dose tested (1 mM). No data are available for local, extravascular concentrations of Sr2+ in patients or animals—but to us, it seems extremely unlikely that they would reach levels as high as the 9 mM Sr2+ used in the paper cited by Xie and Ye [4]. Moreover, it seems inconceivable that such a large amount of Sr2+ could somehow trigger bone formation (a process that involves mineralisation) when a 90-fold lower concentration was able to block bone mineralisation so convincingly.
Thirdly, Drs. Xie and Ye are troubled that we did not include Ca2+ in our culture system. The formulation of the standard DMEM cell culture medium we used is widely available but we are happy to confirm that it does indeed contain Ca2+, added to a concentration of 1.8 mM. This calcium is, of course, required for the abundant matrix mineralisation evident in our control cultures.
Lastly, we certainly did not state in our paper that Sr2+ is a “foe of bone formation”. Rather, as we suggest in the discussion, Sr2+ could potentially exert beneficial effects on bone by acting to limit secondary mineralisation, thus reducing stiffness or brittleness.
References
Xie H, Ye Q (2015) Strontium: friend or foe of bone formation? Osteoporos Int. doi:10.1007/s00198-015-3122-1
Wornham DP, Hajjawi MO, Orriss IR, Arnett TR (2014) Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures. Osteoporos Int 25:2477–2484. doi:10.1007/s00198-014-2791-5
Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468
Chattopadhyay N, Quinn SJ, Kifor O, Ye C, Brown EM (2007) The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol 74:438–447
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Wornham, D.P., Hajjawi, M.O., Orriss, I.R. et al. Strontium and osteoblast function. Osteoporos Int 26, 2215 (2015). https://doi.org/10.1007/s00198-015-3120-3
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DOI: https://doi.org/10.1007/s00198-015-3120-3