Curr Osteoporos Rep (2010) 8:23–27 or osteolysis was found, which resolved after 3 months. Although BMP-2 has been felt to be safe and effective for anterior cervical spine fusion, dysphagia has been noted, possibly related to transient postoperative soft tissue swell- ing, which usually disappears within a few days. Preclinical and clinical safety assessments revealed little evidence of toxic effects and few reports of adverse effects such as ectopic bone formation, bone resorption, swelling, and hematoma. A low level of immunologic reaction has been seen with antibody responses detected in less than 1% of patients. Use of BMPs, however, is limited by their expensive cost. Current use of BMPs requires an open approach; they are currently applied in combination with collagen. Possible new application strategies may include the local and controlled injection of BMPs in combination with a synthetic carrier, such as a calcium phosphate paste. New Delivery Systems in Development for PTH Treatments Nearly 7 years ago, the US Food and Drug Administration approved the first anabolic agent, recombinant human parathyroid hormone (rhPTH) (1–34), the 34 amino acid fragment of PTH, to be given on a daily basis by sub- cutaneous injection for up to 2 years for treating postmen- opausal osteoporosis [22]. PTH is anabolic because it increases bone formation and bone mass, but it also stimulates bone remodeling as part of its action. PTH increases bone formation through several actions, including increasing commitment of mesenchymal stem cells to the osteoblast lineage, increasing osteoblast maturation and possibly life span, and reducing the osteocyte production of sclerostin to further stimulate bone formation. PTH stimu- lation of osteoblastogenesis also increases receptor activator of nuclear factor-κB ligand production, which then stim- ulates osteoclast maturation and activity, increasing bone remodeling overall; however, the overall effect is a positive formation balance. Although rhPTH (1–34) is effective in improving bone strength and incident fracture risk reduc- tion, since it must be administered by daily subcutaneous injection for up to 2 years, a number of osteoporotic patients who might benefit from rhPTH (1–34) treatment do not choose to be treated [23]. Because PTH (1–34) is a peptide hormone, many potential challenges must be overcome to administer it orally. In an attempt to develop a simplier mode of delivery for PTH (1–34), a PTH (1–34) that is delivered by a transdermal microneedle delivery system patch has been developed and now tested in phase 1 and phase 2 clinical trials. The PTH transdermal patch is composed of a small adhesive patch that is coated with hPTH (1–34) on a 25 titanium microneedle array with 1,300 microneedles per hPTH (1–34) patch [24, 25, 26, 27]. A recent phase 2 clinical trial was completed that evaluated the effectiveness of the transdermal hPTH (1–34) compared with rhPTH (1– 34) subcutaneous injections and a placebo patch on bone mineral density (BMD) in postmenopausal women with osteoporosis after 6 months of treatment. A total of 165 patients were enrolled in the study and randomized to an hPTH (1–34) patch of 20 μg, 30 μg, 40 μg, or placebo, or rhPTH (1–34) injections for 6 months. After 6 months of therapy, subjects treated with all doses of the hPTH (1–34) patch and the rhPTH (1–34) given subcutaneously had significant gains in lumbar spine BMD (range, ∼3–5% gain) compared with the placebo patch (−0.02%). In addition, the average gain in total hip BMD in the hPTH (1–34) 40-μg dose group was significantly greater than the placebo group (∼1.5% compared with -0.5%), with no significant change with the 20-µg or 30-µg dose. Changes in the biochemical markers of bone turnover were some- what different between the two deliver systems for PTH. The rhPTH group had a gain in the bone formation marker, P1NP, of nearly 300% and a rise in the bone resorption marker, CTX-1, of nearly 100% over the baseline values. The transdermal patch hPTH (1–34) 40-μg/d group had gains in bone formation by P1NP of only 100%, and CTX- 1 of only about 40% [24]. The explanation for the greater change in BMD of the lumbar spine and hip by the higher doses of the hPTH (1–34) group may be that less bone remodeling was stimulated; however; this is a hypothesis that will require additional studies. One other interesting observation was that the mean plasma concentrations of PTH (1–34) with transdermal delivery peaked after about 5–10 min, whereas the peak was nearly 30 min after the subcutaneous injection, and the serum half-life after the transdermal administration was shorter (∼60 min), whereas it was about 90 min with subcutaneous administration [24]. The different pharmacokinetics between these two delivery systems may explain the changes we observe in bone turnover. However, phase 3 studies of longer duration and more study subjects are needed to elucidate these phase 2 study results. Oral Delivery of PTH A new formulation of PTH (1–34) is being developed as an oral formulation as a way to make this treatment a more convenient option for osteoporotic patients. The oral formulation includes the PTH (1–34) protein and an absorption enhancer, 5-CNAC [28]. A phase 1 study enrolled 34 postmenopausal women and 16 subjects. The subjects were randomized to receive placebo, rhPTH (1– 34), or 1, 2.5, 5, or 10 mg of oral PTH (1–34) formulated