24 Furthermore, SOST-null mice have a high bone mass phenotype [6]. The development of a monoclonal antibody to sclerostin that can be administered subcutaneously has allowed scientists to evaluate the effect of sclerostin blockade on bone metabolism and bone mass. Li et al. [7] treated estrogen-deficient osteopenic rats with biweekly subcuta- neous treatment with 25 mg/kg of a monoclonal antibody to sclerostin for 5 weeks and restored trabecular bone mass to baseline levels. Surface-based histomorphometry deter- mined that the increase in bone mass resulted from an increase in bone mass at all skeletal envelopes, including cancellous, cortical bone sites, and supervertebral sites. The increase in bone mass and change in microarchitecture were associated with improved bone strength in both the appendicular and axial skeleton. Sclerostin (SOST) is thought to function as a paracrine inhibitor of canonical Wnt signaling on the preosteoblast surface by binding to the Wnt coreceptors LRP5 and LRP6 and blocking their colocalization with the frizzled receptor [8]. The bone-forming effects of the SOST antibody in many ways resemble those of high-dose intermittent PTH in rodents. Several studies have reported that sclerostin gene expression and protein levels are reduced in animals treated with daily injections of human parathyroid hormone (hPTH) (1–34) [9]. Preclinical studies with a sclerostin inhibitor appear to be somewhat different from those with hPTH (1–34). For example, all skeletal sites respond to anabolic daily PTH treatment; the trabecular bone is most responsive, followed by the endosteal surface and the periosteal surface. In contrast, inhibition of sclerostin also results in significant bone formation at the periosteal surface. Also, studies find the increases in bone formation induced by antisclerostin antibody, unlike PTH, are not associated with increases in bone resorption in the aged rodent skeleton. Reduced mechanical stimulation leads to disuse osteo- porosis, as seen in bedridden patients and in astronauts. Lin et al. recently [10] reported that SOST knockout mice were resistant to mechanical unloading bone loss. In contrast to wild-type mice [9], Wnt/β-catenin signaling was not altered by unloading in SOST knockout mice. The data suggest a potential major role for sclerostin in mediating the bone response to unloading and propose it may be a promising target for preventing disuse osteoporosis [9]. At this time, the monoclonal antibody to sclerostin in is early phase 2 clinical trials in postmenopausal women with osteoporosis and in fracture healing studies, leaving only phase 1 clinical safety data and short-term preclinical studies. The long-term safety of sclerostin has not been addressed. Additional clinical study data are needed to determine the rapid gain in bone mass is associated with bone of normal strength and architecture, if boney Curr Osteoporos Rep (2010) 8:23–27 overgrowth occurs at areas such as the carpal tunnel resulting in carpal tunnel syndrome, or around the lumbar spine neural foramen resulting in lumbar radiculopathy or spinal stenosis. In summary, treatments based on inhibition of sclerostin may be a powerful way to restore bone strength of the osteoporotic skeleton in our patients and potentially to provide more efficacious protection from hip fracture than current therapies. Bone Morphogenetic Proteins BMPs are members of the transforming growth factor-β superfamily. Bone morphogenic proteins are being used successfully clinically for treating spinal fusion, delayed fracture healing, and nonunion [10]. Multiple in vitro and in vivo studies and clinical trials show a strong effect of BMP-2 and BMP-7 in terms of inducing bone [11–13]. Clinical application is currently restricted in part due to cost. BMP-2 is used for open tibial fractures and spinal fusions, whereas BMP-7 is used for nonunion with limited indication for spinal fusion [14]. BMPs appear to be as good as iliac crest bone graft or even more effective with moderate side effects [10]. There is a need for anabolic agents such as BMP for patients with delayed fracture healing or nonunion. A literature review on tibial fracture healing reveals that 16.7% of patients showed delayed fracture healing or a nonunion, and 11.8% developed malunion with up to 23% requiring operative reintervention [15]. Successful bone healing depends on two factors: 1) mechanical signaling [16], which can be enhanced by biophysical stimulation (eg, ultrasound, shockwaves, and electromagnetic fields), or 2) biological substances (eg, bone grafts, hormones, and growth factors such as BMP) [17]. BMPs appear to be most beneficial for atrophic nonunions, but may also be used for treating hypertrophic nonunions. Treatment of bone defects in nonunion often requires the use of additional grafting material, which may be autogenous bone or potentially, in the future, the use of stem cells. BMP-7 is often used in combination with synthetic carriers based on tricalcium phosphate. BMP-2 is approved for anterior lumbar interbody fusion, but also has shown beneficial results in transforaminal lumbar applica- tion in multiple clinical studies [17, 18]. In posterolateral lumbar fusion, the use of BMP-2 was compared with iliac crest bone graft and showed a significantly higher fusion rate compared with control subjects [19]. Side effects of BMPs are moderate [19–21]. For posterior fusion, heterotopic bone formation was found in the spinal canal close to the cage, raising concerns about safety aspects and that BMP should not be applied too close to the spinal canal. Concerns also have been raised with transforaminal lumbar interbody fusion in which initial vertebral resorption