Burosumab for Tumor-Induced Osteomalacia: Not Enough of a Good Thing.

Abstract

Jan de Beur and colleagues(1) and Imanishi and colleagues(2) recently reported the results of trials of the anti-FGF23 monoclonal antibody medication, burosumab, in adult patients with tumor-induced osteomalacia (TIO). The overall design and results of the studies were very similar; both demonstrated improvement in phosphate levels and fractures, as well as a favorable safety profile that supported the approval of burosumab for TIO by US and Japanese regulatory agencies. While we remain enthusiastic about burosumab use in TIO, we were disappointed by the overall moderate effects: tubular reabsorption of phosphate remained low, mean blood phosphate was barely in the normal range, most fractures persisted after 2 years of treatment (approximately 67%), and new fractures continued throughout much of the study. Histomorphometric assessment of mineralization varied between the two studies and was generally improved, but important measures such osteoid surface/bone surface remained markedly elevated. Effects on measures of quality of life, including pain and function (eg, 6-minute walk test), varied between studies. There was no effect on pain in the Imanishi study but moderate effects in the Jan de Beur study. Overall, effects on clinical outcomes were not significant or moderate. These findings stand in contrast to those found in the study of burosumab in adults with X-linked hypophosphatemia (XLH), a congenital disorder of FGF23 excess, in which effects on blood phosphate and fracture healing were more pronounced within a shorter period (24 versus 96 or 144 weeks; Fig. 1).(3) A likely contributor to the lesser response observed in the TIO studies relative to the XLH study was that the patients with TIO had more severe disease; baseline blood phosphate was 1.6 mg/dL versus 1.9 in TIO versus XLH, and baseline blood intact FGF23 levels in the TIO patients were very high at 416 and 1018 pg/mL (normal ≤30 pg/mL in the setting of hypophosphatemia(4)). However, we think that an additional contributor to the differences was that patients with TIO were undertreated. The mean doses administered in both studies were ≤1 mg/kg q. 4 weeks, in spite of the fact up to 2 mg/kg q. 4 weeks was permitted. Patients with TIO usually have significantly higher FGF23 levels compared with patients with XLH, and in our experience to date in using burosumab in TIO, patients typically require higher doses of medication to achieve the desired effects. Fortunately, burosumab has been approved for doses of up to 2 mg/kg q. 2 weeks in TIO, allowing for doses higher than those allowed and used in these studies. Conventional therapy in TIO (calcitriol or alfacalcidiol and phosphate) can be quite effective if patients can tolerate the relatively high doses of phosphate and manage the complicated regimen. However, with long-term treatment, clinicians are often obligated to accept lower blood phosphate levels to avoid the adverse effects associated with treatment, ie, secondary hyperparathyroidism and hypercalciuria. Because burosumab does not have these limitations, patients have the opportunity to have normal blood phosphate levels and the consequent relatively rapid improvement in bone healing, as was found in XLH. While surgical resection or ablation are usually curative and remain the first line of treatment in TIO, burosumab represents the best option for most patients with unresectable or unlocalizable tumors. No longer bound by the need to keep the blood phosphate just at the lower limit of normal to avoid the untoward consequences of conventional therapy, use of adequate doses of burosumab will likely bring about more rapid resolution of symptoms than predicted in these studies. NIDCR received funding from QED Therapeutics as part of a Cooperative Research and Development Agreement (CRADA). Iris Hartley: Conceptualization; investigation; writing-original draft; writing-review & editing.