The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

Background: Both an elevated posterior tibial slope (PTS) and high-grade anterior knee laxity are often present in patients who undergo revision anterior cruciate ligament (ACL) surgery, and these conditions are independent risk factors for ACL graft failure. Clinical data on slope-correction osteotomy combined with lateral extra-articular tenodesis (LET) do not yet exist. Purpose: To evaluate the outcomes of patients undergoing revision ACL reconstruction (ACLR) and slope-correction osteotomy combined with LET. Study Design: Case series; Level of evidence, 4. Methods: Between 2016 and 2018, we performed a 2-stage procedure: slope-correction osteotomy was performed first, and then revision ACLR in combination with LET was performed in 22 patients with ACLR failure and high-grade anterior knee laxity. Twenty patients (6 women and 14 men; mean age, 27.8 ± 8.6 years; range, 18-49 years) were evaluated, with a mean follow-up of 30.5 ± 9.3 months (range, 24-56 months), in this retrospective case series. Postoperative failure was defined as a side-to-side difference of ≥5 mm in the Rolimeter test and a pivot-shift grade of 2 or 3. Results: The PTS decreased from 15.3° to 8.9°, the side-to-side difference decreased from 7.2 to 1.1 mm, and the pivot shift was no longer evident in any of the patients. No patients exhibited revision ACLR failure and all patients showed good to excellent postoperative functional scores (mean ± SD: visual analog scale, 0.5 ± 0.6; Tegner, 6.1 ± 0.9; Lysholm, 90.9 ± 6.4; Knee injury and Osteoarthritis Outcome Score [KOOS] Symptoms, 95.2 ± 8.4; KOOS Pain, 94.7 ± 5.2; KOOS Activities of Daily Living, 98.5 ± 3.2; KOOS Function in Sport and Recreation, 86.8 ± 12.4; and KOOS Quality of Life, 65.4 ± 14.9). Conclusion: Slope-correction osteotomy in combination with LET is a safe and reliable procedure in patients with high-grade anterior knee laxity and a PTS of ≥12°. Normal knee joint stability was restored and good to excellent functional scores were achieved after a follow-up of at least 2 years.

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