Combination therapy with PTH and DBM cannot heal a critical sized murine femoral defect

Abstract

Orthopaedic surgeons continue to search for cost-effective bone graft substitutes to enhance bone repair. Teriparatide (PTH 1-34) and demineralized bone matrix (DBM) have been used in patients to promote bone healing. We evaluated the efficacy of PTH and DBM in healing a critical sized femoral defect in three lineage-specific transgenic mice expressing Col3.6GFPtopaz (preosteoblastic marker), Col2.3GFPemerald (osteoblastic marker) and a-SMA-Cherry (pericyte/myofibroblast marker). Mid-diaphyseal defects measuring 2 mm in length were created in the central 1/3 of mice femora using a circular saw and stabilized with an alveolar distractor device and cerclage wires. Three groups were evaluated: Group I, PTH 30 mg/kg injection daily, Group II, PTH 30 mg/kg injection daily þ DBM, and Group III, DBM þ 30mL saline injection. PTH was given for 28 days or until the time of sacrifice. Animals were sacrificed at 7, 14, 28, and 56 days. Radiographs at the time of sacrifice were evaluated using a 5-point scaled scoring system. Radiographs showed a lack of healing across all treatment groups at all time points: Group I, 1.57 þ/À 0.68; Group II, 3.00 þ/À 1.29; and Group III, 2.90 þ/À 1.03. Bone formation in the defect as measured by radiographic healing score was significantly better at 56 days in Groups II (p ¼ 0.01) and III (p < 0.01) compared to Group I. Across all treatment groups and time points the defects were largely absent of osteoprogenitor cells based on gross observation of frozen histology and quantitation of cellular based histomorphometric parameters. Quantitation of frozen histologic slides showed a limited osteoprogenitor response to PTH and DBM. Our results suggest that the anabolic agent teriparatide is unable to induce healing in a critical sized mouse femoral defect when given alone or in combination with the DBM preparation we used as a local bone graft substitute.

Single‐dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical‐sized calvarial defect

“…When the intermittent subcutaneous administration of TPTD (15–40 µg/kg/day) has been applied to the bone repair of a critical‐sized defect, various kinds of materials, such as an ACS,23 DBM,21, 23 β‐TCP,24 or PLA20 have been implanted into the defect. The effects of the intermittent subcutaneous administration of TPTD on the repair of a critical‐sized defect after an 8‐ to 9‐week observation period remain controversial; some researchers advocated a significant effect,20, 24 whereas others denied any effect 21, 23.…”

“…The effects of the intermittent subcutaneous administration of TPTD on the repair of a critical‐sized defect after an 8‐ to 9‐week observation period remain controversial; some researchers advocated a significant effect,20, 24 whereas others denied any effect 21, 23. When a biomaterial was implanted into a rat calvarial critical‐sized defect, which was the most similar to that used in the present study, the effects of the intermittent subcutaneous TPTD administration for bone repair were not strongly emphasized 23, 24.…”

“…There are several studies which have applied TPTD to bone defects. 20,21,23,24 These studies employed the intermittent subcutaneous administration of TPTD because it has been established that TPTD has a unique mechanism of action in bone and its intermittent subcutaneous administration leads to bone formation. 17,18 Thus, few studies have used TPTD combined with bone substitutes to investigate bone regeneration in bone defects.…”

“…And several studies were combined with materials, such as absorbable collagen sponge (ACS),23 demineralized bone matrix (DBM),21, 23 β‐tricalcium phosphate (β‐TCP),24 or poly‐lactic acid (PLA) 20. However, the optimal duration and dosage of TPTD for bone regeneration have not yet been established 25.…”

“…19 Many researchers have attempted to repair experimental bone defects using the anabolic effect of the intermittent subcutaneous administration of TPTD. [20][21][22][23][24] And several studies were combined with materials, such as absorbable collagen sponge (ACS), 23 demineralized bone matrix (DBM), 21,23 b-tricalcium phosphate (b-TCP), 24 or poly-lactic acid (PLA). 20 However, the optimal duration and dosage of TPTD for bone regeneration have not yet been established.…”