Combined effect of teriparatide and low-intensity pulsed ultrasound for nonunion: a case report
© Nozaka et al.; licensee BioMed Central Ltd. 2014
Received: 5 March 2014
Accepted: 21 May 2014
Published: 27 May 2014
Low-intensity pulsed ultrasound is a pain-free therapy performed daily at home by the patient and has been shown to promote fracture healing. Teriparatide is a parathyroid hormone preparation that activates osteoblastic bone formation and is also reported to be effective in promoting bony union.
We report the case of a 56-year-old Japanese male with a femoral shaft fracture who underwent intramedullary osteosynthesis nailing initially. He had no radiologic or clinical sign of healing 3 months later and low-intensity pulsed ultrasound was initiated at that time. He was reassessed in another 3 months, with evidence of mild bone consolidation but the fracture gap persisted. Subsequent treatment with human parathyroid hormone was initiated in combination with low-intensity pulsed ultrasound. Full fracture healing was present 6 months after beginning the combination low-intensity pulsed ultrasound and teriparatide. It is hypothesized that the potential additive effects of low-intensity pulsed ultrasound and teriparatide therapy ultimately triggered sufficient bone formation to support osseous union.
The case reported herein is a femoral shaft atrophic nonunion in which traditional interventions failed. Successful fracture healing was finally achieved with low-intensity pulsed ultrasound and teriparatide therapy. This is the first reported case of diaphyseal nonunion with deterioration of bone quality in long bones resolved with teriparatide and low-intensity pulsed ultrasound.
The effect of low-intensity pulsed ultrasound (LIPUS) on the stimulation of bone formation in fracture and in cases of nonunion has been extensively studied . However, there are cases in which bone union is not obtained even with the use of LIPUS, and it is difficult to judge the most appropriate timing for repeat surgery. A large physical, mental and social burden is placed on the patient when repeat surgery is needed. Teriparatide is a recombinant human parathyroid hormone [1–34] (PTH) preparation that is used in the treatment of osteoporosis, and is also reported to be effective in promoting bony union . Teriparatide is effective because of its activation of osteoblastic bone formation . Although both teriparatide and LIPUS have been found to accelerate fracture-healing processes , the effect of the combination of teriparatide and LIPUS in clinical bone fracture management is unclear.
Before teriparatide administration
After teriparatide administration
Serum NTX (NMOLBCE/L)
Serum Hcys (nmol/ml)
Urine Pen (μg/mgCr)
eGFR (ml/min/1.73 m2)
Intermittent administration of human parathyroid hormone (hPTH) has an anabolic effect on bone in humans and is expected to be a potent agent for fracture healing . For nonunion, a second intervention will undoubtedly be necessary, carrying additional risks and potential complications as well as increases in healthcare costs. Therefore, any effective treatment that can solve this situation should be considered. Several recent studies have revealed that intermittent treatment with PTH stimulates osteogenesis in experimental fracture healing of cortical bones and that PTH effects on cortical bone repair are site-specific. Aspenberg et al., in a prospective, randomized, double blind study of conservative fracture treatment for 102 postmenopausal women with distal radial fractures, showed than the time to healing was shorter in a teriparatide 20 mg group than in a placebo group . Warden et al.  reported that teriparatide and LIPUS have contrasting additive, rather than synergistic, effects during fracture healing. Teriparatide primarily increased callus bone mineral content (BMC) without influencing its size, whereas LIPUS increased callus size without influencing BMC in rat studies. Fracture healing is a complex biologic process and is impacted by multiple factors . Watanabe et al.  reported that LIPUS is a relatively new technique for the acceleration of fracture healing in nonunion situations. It has a frequency of 1.5 MHz, a signal burst width of 200 microseconds, a signal repetition frequency of 1 kHz, and an intensity of 30 mW/cm2. The beneficial effect of fracture healing acceleration with LIPUS is considered to be larger in patients with potentially negative factors for fracture healing. LIPUS is a pain-free therapy performed daily at home by the patient with the possibility of avoiding further surgical procedures. This outpatient treatment reduces the length of hospital stays and reduces overall system wide health care expenses. The incidence of delayed union and nonunion is 5% to 10% of all fractures. While LIPUS has beneficial effects on collagen enzymatic cross-link formation, mechanical stress may improve bone quality. Nonunion is a severe complication for the patient, which has a negative impact on quality of life. Treatment for nonunion typically requires a second surgical intervention to provide stability and to stimulate bone healing. These surgeries include locked intramedullary nailing, dynamic compression plating, external fixation with Ilizarov’s principles, and at times autografting. But Brinker et al. reported that all patients with nonunion who met their screening criteria should be referred to an endocrinologist for evaluation because they were likely to have undiagnosed metabolic or endocrine abnormalities that would interfere with bone healing . Two interventions found to accelerate fracture healing processes are conbination of LIPUS and teriparatide without a second surgical intervention in this nonunion patient with deteriorated bone quality. No side effects occurred.
The case reported herein is a femoral shaft atrophic nonunion in which traditional interventions failed. This is the first reported case of diaphyseal nonunion with deterioration of bone quality in long bones resolved with teriparatide and LIPUS. The difference in teriparatide activity on trabecular and cortical bone suggests that teriparatide could accelerate healing in nonunions in diaphyseal nonunion in long bone with deterioration of bone quality. The authors are aware that this is just one case report; thus, new experimental studies and clinical trials with larger groups of subjects must be conducted in order to assess the efficacy of combination teriparatide and LIPUS intervention and the fracture healing.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
There is no substantial direct or indirect commercial financial incentive associated with publishing this article.
- Takikawa S, Matsui N, Kokubu T, Tsunoda M, Fujioka H, Mizuno K, Azuma Y: Low intensity pulsed ultrasound initiates bone healing in rat nonunion fracture model. J Ultrasound Med. 2001, 20 (3): 197-206.PubMedGoogle Scholar
- Oteo-Alvaro A, Moreno E: Atrophic humeral shaft nonunion treated with teriparatide (rh PTH 1–34): a case report. J Shoulder Elbow Surg. 2010, 19 (7): 22-28. 10.1016/j.jse.2010.05.005.View ArticleGoogle Scholar
- Nozaka K, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Shimada Y: Intermittent administration of human parathyroid hormone enhances bone formation union at the site of cancellous bone osteotomy in normal and ovariectomized rats. Bone. 2008, 42 (1): 90-97. 10.1016/j.bone.2007.08.041.PubMedView ArticleGoogle Scholar
- Warden SJ, Komatsu DE, Rydberg J, Bond JL, Hassett SM: Recombinant human parathyroid hormone (PTH 1–34) and low-intensity pulsed ultrasound have contrasting additive effects during fracture healing. Bone. 2009, 44 (3): 485-494. 10.1016/j.bone.2008.11.007.PubMedView ArticleGoogle Scholar
- Saito M, Marumo K, Ushiku C, Kato S, Sakai S, Hayakawa N, Mihara M, Shiraishi A: Effects of alfacalcidol on mechanical properties and collagen cross-links of the femoral diaphysis in glucocorticoid-treated rats. Calcif Tissue Int. 2011, 88 (4): 314-324. 10.1007/s00223-011-9472-6.PubMedView ArticleGoogle Scholar
- Saito M, Fujii K, Marumo K: Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int. 2006, 79 (3): 160-168. 10.1007/s00223-006-0035-1.PubMedView ArticleGoogle Scholar
- Saito M, Marumo K: Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010, 21 (2): 195-214. 10.1007/s00198-009-1066-z.PubMedView ArticleGoogle Scholar
- Saito M, Marumo K, Soshi S, Kida Y, Ushiku C, Shinohara A: Raloxifene ameliorates detrimental enzymatic and nonenzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int. 2010, 21 (4): 655-666. 10.1007/s00198-009-0980-4.PubMedView ArticleGoogle Scholar
- Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC: Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res. 2010, 25 (2): 404-414. 10.1359/jbmr.090731.PubMedView ArticleGoogle Scholar
- Giannotti S, Bottai V, Dell'osso G, Pini E, De Paola G, Bugelli G, Guido G: Current medical treatment strategies concerning fracture healing. Clin Cases Miner Bone Metab. 2013, 10 (2): 116-120.PubMedPubMed CentralGoogle Scholar
- Watanabe Y, Matsushita T, Bhandari M, Zdero R, Schemitsch EH: Ultrasound for fracture healing: current evidence. J Orthop Trauma. 2010, 24 (Suppl 1): 56-61.View ArticleGoogle Scholar
- Brinker MR, O'Connor DP, Monla YT, Earthman TP: Metabolic and endocrine abnormalities in patients with nonunions. J Orthop Trauma. 2007, 21 (8): 557-570. 10.1097/BOT.0b013e31814d4dc6.PubMedView ArticleGoogle Scholar
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