Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing.
ABSTRACT Recent studies have demonstrated that intermittent administration of parathyroid hormone (PTH) enhances osteogenesis (hard callus formation) and increases mechanical strength in experimental fracture healing. Thus far, however, effects of PTH on chondrogenesis (soft callus formation) during fracture healing have not been fully elucidated. In the present study, we analyzed the underlying molecular mechanism by which exogenous PTH would affect chondrogenesis in a model of experimental fracture healing. Unilateral femoral fractures were produced in 2-month-old Sprague-Dawley rats. Daily subcutaneous injections of 10 microg/kg of recombinant human PTH(1-34) [rhPTH(1-34)] were administered over a 28-day period of fracture healing. Control animals were injected with vehicle solution (normal saline) alone. The results showed that, on day 14 after fracture, cartilage area in the PTH-treated group was significantly increased (1.4-fold) compared with the controls, but this increase was not observed at days 21 and 28. In the early stage of chondrogenesis (days 4-7), cell proliferation, expressed as the rate of proliferating cell nuclear antigen-positive cells, was increased in mesenchymal (chondroprogenitor) cells but not chondrocytes in the PTH-treated group compared with controls. In addition, gene expression of SOX-9 was up-regulated in the PTH-treated group on day 4 (1.4-fold), and this was accompanied by enhanced expression of pro-alpha1 (II) collagen (1.8-fold). After 14 days, there were no significant differences between groups in either cell proliferation or the expression levels of cartilage differentiation-related genes (SOX-9, pro-alpha1 (II) collagen, pro-alpha1 (X) collagen and osteopontin). These results suggest that intermittent treatment with low-dose rhPTH(1-34) induces a larger cartilaginous callus but does not delay chondrocyte differentiation during fracture healing.
Article: Parathyroid hormone treatment increases fixation of orthopedic implants with gap healing: a biomechanical and histomorphometric canine study of porous coated titanium alloy implants in cancellous bone.[show abstract] [hide abstract]
ABSTRACT: Parathyroid hormone (PTH) administered intermittently is a bone-building peptide. In joint replacements, implants are unavoidably surrounded by gaps despite meticulous surgical technique and osseointegration is challenging. We examined the effect of human PTH(1-34) on implant fixation in an experimental gap model. We inserted cylindrical (10 × 6 mm) porous coated titanium alloy implants in a concentric 1-mm gap in normal cancellous bone of proximal tibia in 20 canines. Animals were randomized to treatment with PTH(1-34) 5 μg/kg daily. After 4 weeks, fixation was evaluated by histomorphometry and push-out test. Bone volume was increased significantly in the gap. In the outer gap (500 μm), the bone volume fraction median (interquartile range) was 27% (20-37%) for PTH and 10% (6-14%) for control. In the inner gap, the bone volume fraction was 33% (26-36%) for PTH and 13% (11-18%) for control. At the implant interface, the bone fraction improved with 16% (11-20%) for PTH and 10% (7-12%) (P = 0.07) for control. Mechanical implant fixation was improved for implants exposed to PTH. For PTH, median (interquartile range) shear stiffness was significantly higher (PTH 17.4 [12.7-39.7] MPa/mm and control 8.8 [3.3-12.4] MPa/mm) (P < 0.05). Energy absorption was significantly enhanced for PTH (PTH 781 [595-1,198.5] J/m(2) and control 470 [189-596] J/m(2)). Increased shear strength was observed but was not significant (PTH 3.0 [2.6-4.9] and control 2.0 [0.9-3.0] MPa) (P = 0.08). Results show that PTH has a positive effect on implant fixation in regions where gaps exist in the surrounding bone. With further studies, PTH may potentially be used clinically to enhance tissue integration in these challenging environments.Calcified Tissue International 01/2011; 88(4):294-303. · 2.38 Impact Factor
Article: Teriparatide Therapy as an Adjuvant for Tissue Engineering and Integration of Biomaterials.[show abstract] [hide abstract]
ABSTRACT: Critically sized large bone defects commonly result from trauma, radical tumor resections or infections. Currently, massive allografting remain as the clinical standard to treat these critical defects. Unfortunately, allograft healing is limited by the lack of osteogenesis and bio-integration of the graft to the host bone. Based on its widely studied anabolic effects on the bone, we have proposed that teriparatide [recombinant parathyroid hormone (PTH(1-34))] could be an effective adjuvant for massive allograft healing. In support of this theory, here we review studies that have demonstrated that intermittent PTH(1-34) treatment enhances and accelerates the skeletal repair process via a number of mechanisms including: effects on mesenchymal stem cells (MSC), angiogenesis, chondrogenesis, bone formation and remodeling. We also review the current literature on the effects of PTH(1-34) therapy on bone healing, and discuss this drug's long term potential as an adjuvant for endogenous tissue engineering.Journal of Materials Research 06/2011; 4(6):1117-1131. · 1.43 Impact Factor
Article: A fracture does not adversely affect bone mineral density responses after teriparatide treatment.[show abstract] [hide abstract]
ABSTRACT: Fracture leads to local and systemic catabolic physiologic changes. As teriparatide is an agent used to treat osteoporosis in patients with fragility fractures, it is unclear whether teriparatide treatment alters bone mineral density (BMD) and bone markers when given to patients with fractures. We asked whether BMD and bone marker responses would be blunted in patients with fractures placed on teriparatide after fracture compared with patients without fractures on teriparatide. We retrospectively collected data from 141 patients treated with teriparatide for osteoporosis. Seventy-seven patients received teriparatide after fractures (fracture group), whereas 64 were treated for other indications (nonfracture group). We determined BMD at the lumbar spine and at the proximal femur before and 12 and 24 months posttreatment. Bone markers (urine N-telopeptide [urine NTX], bone-specific alkaline phosphatase [BALP]) were measured at baseline and 3, 12, and 24 months posttreatment. Mean lumbar spine and hip BMDs at last followup increased from baseline with no differences between groups to approximately 9% and 4% at 24 months, respectively. Both bone markers increased from baseline in the nonfracture group, peaking at 12 months. For the fracture group, only urine NTX increased at 3 and 12 months posttreatment. Although the peak levels of both bone markers in the nonfracture group were greater, there was no difference between the two groups. Fracture does not have a negative effect on the BMD and bone marker responses to teriparatide treatment. Clinicians should anticipate comparable BMD responses when treating patients with teriparatide for osteoporotic fractures and for other indications. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.Clinical Orthopaedics and Related Research 08/2011; 470(3):927-36. · 2.53 Impact Factor