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jbm > Volume 22(4); 2015 > Article
Im and Lee: Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review

Abstract

Background

Bisphosphonates (BPs) are the most commonly used anti-osteoporotic drugs, which have been proven to reduce the risk of osteoporotic fractures. However, use of BPs, particularly for long periods of time, is associated with an increased risk of atypical femoral fracture (AFF). Healing of BP-associated AFF is usually delayed because of suppressed bone turnover. Teriparatide (TPTD), a recombinant form of parathyroid hormone (PTH), enhances bone healing in patients with delayed healing or non-union.

Methods

In this study, we summarized and performed a systemic review of the published literature on treatment of AFF using TPTD.

Results

Although there is a lack of level 1 studies on the evidence of TPTD in promoting bone union in AFFs, this systemic review of the available literature revealed that TPTD works positively in AFFs, and we put together the evidence that TPTD is a viable treatment option for enhancing fracture healing in AFFs.

Conclusions

While anecdotal evidence of beneficial effects of TPTD on fracture healing offer limited guidance for clinical decision making, a better understanding of the role of TPTD in fracture healing may be elucidated with future prospective trials.

INTRODUCTION

Bisphosphonates (BPs) are the most commonly used anti-osteoporotic drugs, which have been proven to reduce the risk of osteoporotic fracture. BPs are also known to improve quality of life in patients with osteoporosis [1] and reduce mortality in patients who have sustained hip fractures.[2] However long term use of BPs is associated with an increased risk of atypical femoral fracture (AFF).[3,4] AFFs are transverse or oblique stress fractures without comminution occurring in the cortex of the subtrochanteric region or shaft of femur.[5,6,7]
Anti-resorptive agents including BPs reduce the rate of bone remodeling, therefore slowing the progression of structural loss in bone matrix. Bone matrix then undergoes more complete secondary mineralization rather than being removed and replaced with younger and less mineralized bone matrix,[8] which paradoxically makes bones more brittle because it cannot absorb energy by deformation when loaded. Subsequently, the energy applied to the bone is dissipated by micro-cracking.[9] As seen in prolonged BP administration, microcracks propagate and lengthen with less resistance in homogeneously mineralized bone matrix.[10] In addition, reduced removal of bone microdamage increases occurrence and propagation of microcracks and compromises the material strength of bone, leading to increased occurrence of stress fractures.[11]
Because of suppressed bone turnover, healing of BP-associated AFF is also usually delayed.[12,13] Teriparatide (TPTD), a recombinant form of parathyroid hormone (PTH) and an anti-osteoporotic agent with potent bone-forming effects,[14,15] enhances bone healing in patients with delayed healing or non-union.[16] A number of studies have demonstrated beneficial effects of TPTD on fracture healing in various animal models, both radiographically and histologically.[17,18,19,20,21] However, there is only limited data for humans currently available for TPTD in fracture healing.[22] When AFF is diagnosed in a patient, the use of BPs as anti-osteoporotic drug is stopped and replaced with TPTD or a selective estrogen receptor modulator. The positive effect of TPTD on fracture healing has prompted the use of TPTP to promote the union of AFF as well.[23,24] Although a number of narrative literature reviews exist elaborating on the role of TPTD in AFF, there is a lack of systematic review of the literature on the subject. In this study, we summarized and performed an in-depth review from published literature on the treatment of AFF using TPTD.

METHODS

We performed searches of PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews (CDSR) using the search terms "TPTD", "PTH", "atypical fracture", "atypical femoral fracture", and "healing." We also screened the references of the searched articles for additional information. Due to the limited amount of literature available on this topic, case reports and case series were also included in the final analysis. Exclusion criteria included articles not relevant to the use of TPTD in AFF, non-English articles, stand-alone abstracts, meeting presentations, commentaries, and review articles.
Searching the aforementioned databases yielded 72 results. Two authors independently read and reviewed the abstracts and full text of the retrieved articles. Eleven articles were deemed appropriate for our study. These included 1 article reporting results from a prospective study, 3 articles from retrospective case series, and 7 case reports. These articles were then analyzed in detail (Fig. 1).

RESULTS

Gomberg et al.[25] first reported a subtrochanteric AFF in a postmenopausal woman with a 13-year history of continuous alendronate therapy that was treated with TPTD, vitamin D, and calcium. However, thigh pain, presented as an initial symptom, intensified, and the magnetic resonance imaging (MRI) showed the appearance of fractures worsening. TPTD treatment commenced, and 6 months later, a repeat MRI showed decreased edema at the fracture sites with faint cortical bridging. Six other reports had similar findings. In all, 7 case reports with 8 patients and 11 AFFs (7 incomplete, 4 complete) were described. All the patients were elderly Asian or Caucasian females (age ranging from 63 to 84 years). TPTD treatment started at 1 to 11 months after detection of AFF. TPTD was administered for 3 to 24 months. Daily subcutaneous (SC) injection was the most common form of treatment (4 patients) although Weekly injection was used in 1 patient. Combination treatments included intramedullary nailing in acute fracture setting or as a prophylaxis (for 4 AFF cases), prophylactic locking plate (for 2 AFFs), vitamin D and calcium supplementation in 2 patients. Fracture healing was observed after 3 to 21 months after TPTD treatment. One patient was additionally treated with strontium ranelate because of persistent discomfort after 24 months of TPTD treatment. [25,26,27,28,29,30,31]
Miyakoshi et al.[32] retrospectively reviewed the medical records of 45 consecutive AFFs in 34 Japanese patients who had received oral BPs (alendronate or risedronate) for osteoporosis before AFF and had been followed for >12 months (range, 12 to 90). Thirty-seven complete or incomplete AFFs (82%) were treated surgically and 8 incomplete AFFs (18%) were treated conservatively. Based on TPTD use after fracture, these AFFs were divided into non-TPTD (n=24) and TPTD (n=21) treated groups. In subanalyses for all AFFs treated surgically, mean time to fracture healing was significantly better in the TPTD group (5.4±1.5 months) than in the non-TPTD group (8.6±4.7 months, P=0.012), and the frequency of delayed healing or non-union was significantly lower in the TPTD group than in the non-TPTD group (P=0.014). On the other hand, subanalyses for incomplete AFFs treated conservatively showed no significant differences between the groups.[32]
Saleh et al.[33] retrospectively examined 10 patients with a total of 14 incomplete AFFs. Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and TPTD. All these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only 2 of these were treated successfully with conservative management including TPTD. Six of 8 patients with a radiolucent line opted for surgical prophylaxis after 3 months of conservative management, whereas 1 patient underwent surgical prophylaxis without a trial of conservative management.[33]
Miller and McCarthy [34] studied 15 clinic patients with AFF who underwent quantitative bone histomorphometry both before and after 12 months of TPTD (20 µg SC/day). All patients had been on long-term alendronate (mean=7 years, range, 6 to 11 years) and had already had intramedullary rods placed when first seen (6 weeks to 7 months after rod placement). Discontinuation of BP and administration of TPTD was associated with an increase in all three dynamic histomorphometric parameters including bone formation, mineralizing surface, and mineral apposition. Baseline bone turnover markers did not correlate with the baseline histomorphometry.[34]
Chiang et al.[23] performed a prospective study involving 14 consecutive patients presenting during 2 years with AFF. All patients were offered TPTD therapy unless contraindicated. Of these 14 patients, 6 had unilateral and 8 had bilateral AFFs. Five patients agreed on the treatment with TPTD, one following a stress fracture and 4 patients because of persisting fracture non-union and ongoing pain. The remaining 9 patients (5 with complete, 4 with incomplete fractures) were not treated due to contraindications to use of TPTD. Twenty µg of daily TPTD given SC for 6 months to 5 patients was associated with a 2 to 3-fold increase in bone remodeling markers (P=0.01) and fracture healing. Of 9 patients managed conservatively or surgically without TPTD, 6 had poor fracture healing with ongoing pain, one sustained a contralateral atypical fracture, and one had fracture union after 1 year (Table 1).[23]

DISCUSSION

AFF wreaks catastrophe on osteoporotic patients who have had prolonged BP treatment. The over-mineralized fracture ends in these patients pose challenge to fracture union because of delayed bone remodeling. TPTD, which is a bone-forming agent used for nonunion, has become a key therapeutic agent for promoting bone union in AFF. A recent paper elucidates a working mechanism that can possible explain the action of TPTD in AFFs. Murphy et al. [35] employed a mixture of traceable BPs, namely fluorescent-labeled pamidronate and radiolabeled zoledronic acid in an animal study. The traceable BPs were dosed in Wistar rats for models of normal growth and closed fracture repair. Consistent with increased BP remobilization with PTH (1-34) (a form of TPTD), there was a significant decrease in fluorescence in both the long bones and in the fracture callus in PTH-treated animals compared with controls rats. Increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH (1-34) increased bone turnover as well as BP turnover.
Although there is a lack of level 1 study on the evidence of TPTD in promoting bone union in AFFs, our systemic review of the literature reveals that TPTD works positively for AFFs. Case reports continue to provide anecdotal evidence of the efficacy of PTH for fracture healing but are of limited utility in guiding clinical decision making. The prospective study of Chiang et al.[23] shows the advantages of using TPTD in AFFs that have inherent difficulty in achieving fracture healing. The results from the study of Miyakoshi et al. [32] show that TPTD administration shortens the union time and reduces the incidence of delayed or nonunion in surgically treated AFFs while it is undetermined in non-surgical cases. The series of Saleh et al.[33] shows that incomplete fractures without radiolucent lines are responsive to TPTD alone whereas those with radiolucent line needed intramedullary nailing. These results imply that TPTD works best when the fracture site is stable, either inherently or with surgical fixation.
Addressing fracture healing in AFFs is very important, and it can be achieved using anabolic therapy. We have conducted a systematic review of the literature on the use of TPTD to enhance fracture healing. Our study has the limitation of depending on the quality of the studies it analyzed. Due to limited available evidence on TPTD use for AFFs, we relied considerably on case reports and retrospective case series in this study. While anecdotal evidence of beneficial effects of TPTD on fracture healing offer limited guidance for clinical decision making, a better understanding of the role of TPTD in fracture healing may be elucidated with future prospective trials. As such, TPTD is currently a viable treatment option to enhance fracture healing in AFFs.

DECLARATIONS

No potential conflict of interest relevant to this article was reported.

References

1. Iwamoto J, Makita K, Sato Y, et al. Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis. Osteoporos Int 2011;22:2735-2742.
crossref pmid pdf
2. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799-1809.
crossref pmid
3. McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013;126:13-20.
crossref pmid
4. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014;29:1-23.
crossref pmid
5. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010;25:2267-2294.
crossref pmid
6. Koh JS, Goh SK, Png MA, et al. Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture? J Orthop Trauma 2010;24:75-81.
crossref pmid
7. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 2011;305:783-789.
crossref pmid
8. Seeman E. Bone morphology in response to alendronate as seen by high-resolution computed tomography: through a glass darkly. J Bone Miner Res 2010;25:2553-2557.
crossref pmid
9. Currey JD. Bone architecture and fracture. Curr Osteoporos Rep 2005;3:52-56.
crossref pdf
10. Karim L, Vashishth D. Role of trabecular microarchitecture in the formation, accumulation, and morphology of microdamage in human cancellous bone. J Orthop Res 2011;29:1739-1744.
crossref pmid pmc
11. Currey J. Structural heterogeneity in bone: good or bad? J Musculoskelet Neuronal Interact 2005;5:317
pmid
12. Egol KA, Park JH, Rosenberg ZS, et al. Healing delayed but generally reliable after bisphosphonate-associated complete femur fractures treated with IM nails. Clin Orthop Relat Res 2014;472:2728-2734.
crossref pmid
13. Thompson RN, Phillips JR, McCauley SH, et al. Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals. J Bone Joint Surg Br 2012;94:385-390.
crossref pmid
14. Gallacher SJ, Dixon T. Impact of treatments for postmenopausal osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate, and denosumab) on bone quality: a systematic review. Calcif Tissue Int 2010;87:469-484.
crossref pmid pdf
15. Miyakoshi N. Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis. Curr Pharm Des 2004;10:2615-2627.
crossref pmid
16. Pietrogrande L, Raimondo E. Teriparatide in the treatment of non-unions: scientific and clinical evidences. Injury 2013;44(Suppl 1):S54-S57.
crossref pmid
17. Alkhiary YM, Gerstenfeld LC, Krall E, et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am 2005;87:731-741.
pmid
18. Bostrom MP, Gamradt SC, Asnis P, et al. Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy. Bone 2000;26:437-442.
crossref pmid
19. Komrakova M, Stuermer EK, Werner C, et al. Effect of human parathyroid hormone hPTH (1-34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats. Bone 2010;47:480-492.
crossref pmid
20. Mognetti B, Marino S, Barberis A, et al. Experimental stimulation of bone healing with teriparatide: histomorphometric and microhardness analysis in a mouse model of closed fracture. Calcif Tissue Int 2011;89:163-171.
crossref pmid pdf
21. Rowshan HH, Parham MA, Baur DA, et al. Effect of intermittent systemic administration of recombinant parathyroid hormone (1-34) on mandibular fracture healing in rats. J Oral Maxillofac Surg 2010;68:260-267.
crossref pmid
22. Aspenberg P, Genant HK, Johansson T, et al. 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;25:404-414.
crossref pmid
23. Chiang CY, Zebaze RM, Ghasem-Zadeh A, et al. Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy. Bone 2013;52:360-365.
crossref pmid
24. Lee YK, Ha YC, Kang BJ, et al. Predicting need for fixation of atypical femoral fracture. J Clin Endocrinol Metab 2013;98:2742-2745.
crossref pmid pdf
25. Gomberg SJ, Wustrack RL, Napoli N, et al. Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a postmenopausal woman with a 13-year history of continuous alendronate therapy. J Clin Endocrinol Metab 2011;96:1627-1632.
crossref pmid
26. Carvalho NN, Voss LA, Almeida MO, et al. Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide. J Clin Endocrinol Metab 2011;96:2675-2680.
crossref pmid
27. Fukuda F, Kurinomaru N, Hijioka A. Weekly Teriparatide for Delayed Unions of Atypical Subtrochanteric Femur Fractures. Biol Ther 2014;
crossref
28. Huang HT, Kang L, Huang PJ, et al. Successful teriparatide treatment of atypical fracture after long-term use of alendronate without surgical procedure in a postmenopausal woman: a case report. Menopause 2012;19:1360-1363.
crossref pmid
29. Lampropoulou-Adamidou K, Tournis S, Balanika A, et al. Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration. Hormones (Athens) 2013;12:591-597.
crossref pmid
30. Tarazona-Santabalbina FJ, Aguilella-Fernández L. Bisphosphonate long-term treatment related bilateral subtrochanteric femoral fracture. Can teriparatide be useful? Aging Clin Exp Res 2013;25:605-609.
crossref pdf
31. Tsuchie H, Miyakoshi N, Nishi T, et al. Combined effect of a locking plate and teriparatide for incomplete atypical femoral fracture: two case reports of curved femurs. Case Rep Orthop 2015;2015:213614
crossref pmid pmc pdf
32. Miyakoshi N, Aizawa T, Sasaki S, et al. Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide. J Bone Miner Metab 2015;33:553-559.
crossref pmid pdf
33. Saleh A, Hegde VV, Potty AG, et al. Management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. HSS J 2012;8:103-110.
crossref pmid pmc pdf
34. Miller PD, McCarthy EF. Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and after teriparatide administration. Semin Arthritis Rheum 2015;44:477-482.
crossref pmid
35. Murphy CM, Schindeler A, Cantrill LC, et al. PTH(1-34) treatment increases bisphosphonate turnover in fracture repair in rats. J Bone Miner Res 2015;30:1022-1029.
crossref pmid
Fig. 1

Flow chart of article selection process.

jbm-22-183-g001.jpg
Table 1

Summary of the published studies referred in the report

jbm-22-183-i001.jpg

TPTD, teriparatide; PTH, parathyroid hormone; SC, subcutaneous; Rt., right; Lt., left; IM, intramedullary; CTX, C-terminal telopeptides of type I collagen; mo, month; yr, year; wk, week; wkly, weekly; F, female; M, male; AFF, atypical femoral fracture.



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