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Letter to the Editor Regarding “Durability and Delayed Treatment Effects of Zoledronic Acid on Bone Loss After Spinal Cord Injury: A Randomized, Controlled Trial”

To the Editor: We read with interest the original research published in JBMR titled “Durability and delayed treatment effects of zoledronic acid on bone loss after spinal cord injury: a randomized, controlled trial” by Edwards and colleagues. The investigators have ardently analyzed and presented their findings on sublesional bone loss in spinal cord injury (SCI) among war veterans from a single center. Spinal cord injury is associated with significant morbidity and sometimes lifelong disability. The complications of prolonged immobilization can range from deep venous thrombosis, pressure ulcers, urinary infections, and bone loss. Although most complications are easily identified with telltale signs and their emergent presentation, osteoporosis often goes unrecognized. This is evenmore important because the first 2 weeks after initial injury is recognized as the most vulnerable period for decreased bone formation. When the consequences are so grave, postSCI bone loss is also an emergency, and timely and adequate measure will go a long way in reducing morbidity in these patients. Fragility fractures are a serious complication of osteoporosis and can prolong immobilization in these patients. Stronger bones can be the best gift to these patients when they spring back to their feet. We therefore compliment the authors for addressing the issues of durability and timely treatment benefits in patients with SCI. While we agree with these two core issues presented in this study, there are a few points that we wish to raise. First, the authors have stated that of the total injuries, most SCI were cervical (56%). Analysis of lower limbs only would be inappropriate for this large group, who would mostly be presenting with quadriparesis or quadriplegia. These patients would be at high risk of fragility fractures involving the upper limbs, particularly during transportation and maneuvering. Considering this evaluation of bone loss in the upper limbs with the same modalities is prudent and would give a better estimate of the morbidity. Bonemineral density (BMD)measured at the distal radius or a whole-body BMD can serve this purpose. Second, we point out the duration of follow-up chosen by the investigators. A 2-year follow-up seems appropriate but may be inadequate considering prolonged and sometimes lifelong immobilization in these patients. Although the findings covering the initial 2 years after injury seem reassuring, a look beyond the 2-year period is also advised. There is some controversy about continued bone loss beyond the 2to 5-year period after initial injury. Whereas some studies have demonstrated that bone loss plateaus after 3 to 5 years, others have shown a steady decremental loss in BMD. Contrary to popular belief, bone mineral concentration (BMC) at the femoral shaft stabilizes at a mean post-injury duration of 6.8 years. Looking beyond 2 years would give better insight into the long-term effects of single or yearly zoledronic acid infusion. In the landmark HORIZON trial, postmenopausal womenwith osteoporosis were followed for 36 months and the recommendations finally made advocate yearly zoledronic acid infusions for postmenopausal osteoporosis. The effects of zoledronic acid may persist for up to 2 years, and some researchers have recommended zoledronic acid infusion in postmenopausal women at 2-year intervals. Considering that the authors have agreed in certain aspects that the nature of bone loss in SCI is similar to postmenopausal osteoporosis, longer follow-up may end up suggesting similar management in both these conditions. Third, we consider the findings around the knee joint at 1 and 2 years. In the present study, the initial improvement at 12 months in CT scan parameters at the knee joint were not maintained at 24 months. This is a real setback because it amounts to failure in protecting the most vulnerable area for fragility fractures in SCI patients. There is a great deal of promising research going on in use of bisphosphonates, particularly zoledronic acid, in the management of knee pain and effects on structural changes in the knee joint. The results of bisphosphonate efficacy in knee are conflicting, but some studies have shown positive results. Further research in this aspect is required before ruling out bisphosphonates for knee joint improvement. Another point wewish to highlight is the critical role sclerostin plays in SCI-induced bone loss. Several studies have demonstrated increased levels of sclerostin in patients with disability and immobilization. Moreover, sclerostin levels are highest post-injury and decrease in chronic SCI patients. Lastly, the high incidence of adverse effects (98%) in the present study is also striking. It is known from previous usage and also from our experience that intravenous zoledronic acid