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Case report
Tensile type of stress fracture neck of femur: role of teriparatide in the process of healing in a high risk patient for impaired healing of fracture Rajesh Malhotra Sanjay Meena Vijay Kumar Digge
Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, India
Address for correspondence: Vijay Kumar Digge, Senior Resident Department of Orthopaedics All India Institute of Medical Sciences Ansari Nagar, New Delhi - 110029, India Phone: 919968397331 E-mail: [email protected]
Summary Neck of femur stress fractures, whilst representing only around 8% of stress fractures is associated with a high morbidity. Radiographically, stress fractures of neck of femur are classified into compression and tensile type. Tensile type is notorious for displacement and hence prophylactic surgery is indicated, unlike stable compression fracture. Currently recombinant Parathyroid Hormone (PTH) is used in the treatment of osteoporosis. More recently, many animal studies suggest that the recombinant PTH is helpful to achieve fracture union in normal model and in impaired fracture healing model. We achieved union in a 62-year-old postmenopausal female with tensile type of fracture neck of femur, who had multiple comorbidities for impaired healing of fracture, without any surgical intervention using systemic recombinant PTH. KEY WORDS: stress fracture; neck femur; recombinant parathyroid hormone; teriparatide.
ment of or augmentation of fracture healing. There are few studies published in the literature in last decade regarding the role of recombinant PTH to achieve union in both normal model and impaired model for fracture healing. However, most of the published studies were on animal models. We achieved union in a 62-year-old female with tensile type of fracture neck of femur, who had multiple comorbidities for impaired healing of fracture, without any surgical intervention using systemic recombinant PTH.
Case report A 62-year-old post menopausal female presented in the outpatient department of orthopedics with pain in her right hip and groin which was aggravated upon weight bearing since past 4 weeks. On enquiry, she revealed there was no history of fall or trauma. She was diabetic patients and was on oral hypoglycemic drugs since 3 years. She never smoked cigarettes or drank alcohol. Routine radiographs were within normal limit except for osteopenia. Her BMD measurement was performed and her T score was found to be -6.9. Serum analysis was within normal limits. She was advised bed rest and analgesics but there was no improvement in her symptoms. After 2 weeks an MRI of pelvis with both hips was taken, which showed (Figure 1) the presence of fracture line extending obliquely from superolateral aspect of neck of femur with edema, suggestive of tensile type of stress fracture NOF. Patient was advised strict non weight bearing mobilization and it was decided to give teriparatide subcutaneous injection 20 microgram daily. She was also supplemented with oral Vitamin D (60,000IU/week) and calcium supplement (500 mg b.i.d). Gradually there was improvement in patient’s symptoms. Three months later a repeat MRI (Figures 2, 3) showed complete healing of the fracture line with resolution of the edema.
Discussion Introduction The exuberant information of the literature describing the stress fracture neck of femur (NOF) provides very little information on the treatment for the same in individuals with multiple risk factors for fracture healing. There is no consensus among the orthopedic surgeons to manage these patients. Some surgeons recommend immobilization others recommend prophylactic surgery in the form of screw fixation, but both modalities may result in non union of fracture because of impaired healing. Based on the anabolic effects of teriparatide, there is some evidence for its use in the treatment of fresh fractures and non unions. There is a tremendous research and debate going on as far as teriparatide (recombinant PTH) is concerned in the treat-
210
The first description of femoral neck stress fracture in the literature was published by Asal (1) in the German Arch für Klinische Chirurgie, in 1936. Since that time, numerous articles have recognized these fractures as difficult entities to treat. Stress fractures of the femoral neck are uncommon injuries, comprising group of injuries that result from cyclic mechanical stresses. They occur either as fatigue or insufficiency fractures. Stress fractures around neck of femur are seen in two distinct populations: 1) young, healthy, active individuals who are involved in high demanding activities; and 2) the elderly, who have osteoporosis (2). Fatigue fractures frequently occur because of athletic activities. Competitive runners, ballet dancers and military recruits are classically associated with these types of fractures (3). Elderly individuals are more often Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
13-Meena_- 28/01/14 17:56 Pagina 211
Tensile type of stress fracture neck of femur: role of teriparatide in the process of healing in a high risk patient for impaired healing of fracture
Figure 1 - Plane radiograph of pelvis with bilateral hip showing osteopenia.
Figure 2 - MRI of pelvis with bilateral hip (both T1 & T2 weighted) showing tensile type of fracture with bone edema.
culprits for insufficiency type of stress fractures, which occur during normal activities of daily living. Osteoporosis, osteomalacia, rheumatoid arthritis, diabetes, hyperparathyroidism, scurvy and irradiation all are associated with an increased risk of femoral neck insufficiency fractures (3, 4). First and most commonly used classification system for stress fracture neck of femur was given by Devas (5) in 1965. He classified stress fracture neck of femur into two types that differed radiographically and had diverse clinical progression and outcomes; namely compression and tension type of stress fractures. The compression type of femoral neck stress fracture has radiographic changes in the form of internal callus formation on the inferior femoral neck without apparent cortical disruption; this type of fracture is thought to mechanically stable. The transverse type of femoral neck stress fracture is directed perpendicular to the line of force transmission in the femoral neck, originates at the superior surface of the femoral neck, and results from tension; this type of fracture is inherently unstable and at increased risk for displacement. Magnetic Resonance imaging (MRI) is 100% sensitive, specific and accurate in identifying a femoral neck stress fracture (6). In our patient it was a tensile type of fracture which was diagnosed with MRI. The plain radiographs initially taken failed to detect the fracture. Compression type fractures of the femoral neck are mechanically more stable, so they can be managed with non operative treatment (6). Tension types of stress fractures are potentially unstable and they require with the use of Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
Figure 3 - MRI of pelvis with bilateral hip (both T1 & T2 weighted) showing healing of fracture with resolution of bone edema.
internal fixation (2, 5) in young individual, whereas in elderly individuals surgical option include open reduction internal fixation or prosthetic replacement. Our patient had a classical indication for surgery but surgery was deferred as the patient had all the risk factors which would lead to impaired healing, including old age, estrogen deficiency and diabetes mellitus. The severe osteoporosis itself would not have provided adequate hold of the implant and there may have been a failure of desired function of the implant. So it was decided to manage the patient conservatively with non weight bearing mobilization and teriparatide. To improve the BMD, she was also supplemented with oral Vitamin D (60,000IU/week) and calcium supplement (500 mg b.i.d). We expected that the PTH treatment would provide the necessary stimulus needed to increase the number and quality of osteoblasts and osteoclasts to form basic multicellular units (BMU) at the stress fracture site and bring about the healing. Most complications after femoral neck stress fracture are associated with fracture displacement (7) or delay in diagnosis (8). As tensile type of fractures are highly unstable and is prone to displacement, hence more chances of complication related to fracture displacement (7-9) (osteonecrosis, non union and malunion) than compressive type. There are several conditions that can impair fracture-healing including diabetes, glucocorticoid treatment, osteoporosis, advanced age, and metabolic bone disease (10). Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis (11), and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures. At the time of writing, PTH 1-34 (teriparatide) is the FDA-approved form of PTH for use in treating osteoporosis in humans. While the animal studies performed to date concluded that the systemic PTH treatment can improve healing in advancing age, in ovariectomized rats. The most prominent benefits from PTH would be from its potential use on patients in whom bone repair may be delayed or impaired. Andreassen et al. (12) reported results of a study comparing fracture-healing in two to three-month old rats with aged (twenty-seven-month-old) rats treated with intermittent PTH 1-34 (200 mg/day) or vehicle alone. The study also noted that a reduction in the number of osteoprogenitor cells and/or a diminished rate of maturation of pre-osteoblasts to osteoblasts is correlated with old age. Overall remodelling capacity declined in association with this diminished osteoblastic activity,
211
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R. Malhotra et al. raising the question of whether older animals would respond to PTH as robustly as younger animals. PTH treatment of healing fractures in these older rats led to both increased callus formation and increased mechanical strength by twentyone days after fracture. The ovariectomized rat is a commonly used animal model of osteoporosis in which the operative removal of the ovaries mimics the metabolic condition of loss of estrogen in postmenopausal women. Jahng and Kim (13) have used ovariectomized rats to test the efficacy of PTH in fracture repair in this model of estrogen deficiency. The results of this study demonstrated that an impaired fracture-healing response in the ovariectomized animals, including an inhibition of mineralized bone formation and a reduction of trabecular bone formation at the later stages of repair. Both PTH treatment groups displayed increased callus formation with high-dose PTH, with callus formation approaching that seen in sham-operated control animals in terms of percent of trabecular bone volume in the callus. These results support the conclusion that PTH can act as an anabolic treatment for fracture repair in an ovariectomized model of osteoporosis. The studies (14, 15) on the rat model clearly demonstrate that systemic PTH treatment leads to increased callus volumes, rates of new bone formation, and restoration of mechanical competence in the models of both normal and impaired fracture repair. Considering these teriparatide results in a rat model of long bone fractures and our finding in a severe osteoporotic, postmenopausal woman with stress fracture neck of femur, we think that sufficient information has accumulated that we can safely suggest that teriparatide therapy can be included in a list of possible treatment modalities of adult patients with atypical fractures which are not complete and in high risk individual for fracture healing. Moreover, assuming that our results can be duplicated, we recommend that controlled trials of teriparatide can be conducted to test whether it produces consistent healing of this apparently uncommon fracture in a high risk individual for impaired fracture healing.
212
References 1. 2. 3. 4. 5. 6.
7.
8. 9. 10. 11.
12.
13.
14.
15.
Asal D. Überlastungsschäden am Knochensystem bei Soldaten. Arch für Klinische Chirurgie 1936;186:511-522. Egol KA, Koval K J, Kummer F, et al. Stress Fractures of the Femoral Neck. Clin Orthop Relate Res 1998 Mar;348:72-78. Daffner RH, Pavlov H. Stress fractures: Current concepts. Am J Roentgenol 1992;159:245-252. Tountas AA. Insufficiency stress fractures of the femoral neck in elderly women. Clin Orthop Relate Res 1993;292:202-209. Devas MB. Stress fractures of the femoral neck. J Bone Joint Surg 1965;47B:728-737. Shin AY, Morin WD, Gorman JD, et al. The superiority of magnetic resonance imaging in differentiating the cause of hip pain in endurance athletes. Am J Sports Med 1996;24:168-176. Visuri T, Vara A, Meurman KOM. Displaced stress fractures of the femoral neck in young male adults: A report twelve operative cases. J Trauma 1988;28:1562-1569. Johansson C, Ekenman I, Tornkvist H, et al. Stress fractures of the femoral neck in athletes. Am J Sports Med 1990;18:524-528. Fullerton LR, Snowdy HA. Femoral neck stress fractures. Am J Sports Med 1988;16:365-377. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br 2007;89:1553-1560. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007;146:326-339. Andreassen TT, Fledelius C, Ejersted C, et al. Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 2001;72:304-307. Jahng JS, Kim HW. Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 2000;23:1089-1094. Nakajima A, Shimoji N, Shiomi K, et al. Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34). J Bone Miner Res 2002;17:2038-2047. Nakazawa T, Nakajima A, Shiomi K, et al. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 2005;37:711-719.
Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
Case report
Tensile type of stress fracture neck of femur: role of teriparatide in the process of healing in a high risk patient for impaired healing of fracture Rajesh Malhotra Sanjay Meena Vijay Kumar Digge
Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, India
Address for correspondence: Vijay Kumar Digge, Senior Resident Department of Orthopaedics All India Institute of Medical Sciences Ansari Nagar, New Delhi - 110029, India Phone: 919968397331 E-mail: [email protected]
Summary Neck of femur stress fractures, whilst representing only around 8% of stress fractures is associated with a high morbidity. Radiographically, stress fractures of neck of femur are classified into compression and tensile type. Tensile type is notorious for displacement and hence prophylactic surgery is indicated, unlike stable compression fracture. Currently recombinant Parathyroid Hormone (PTH) is used in the treatment of osteoporosis. More recently, many animal studies suggest that the recombinant PTH is helpful to achieve fracture union in normal model and in impaired fracture healing model. We achieved union in a 62-year-old postmenopausal female with tensile type of fracture neck of femur, who had multiple comorbidities for impaired healing of fracture, without any surgical intervention using systemic recombinant PTH. KEY WORDS: stress fracture; neck femur; recombinant parathyroid hormone; teriparatide.
ment of or augmentation of fracture healing. There are few studies published in the literature in last decade regarding the role of recombinant PTH to achieve union in both normal model and impaired model for fracture healing. However, most of the published studies were on animal models. We achieved union in a 62-year-old female with tensile type of fracture neck of femur, who had multiple comorbidities for impaired healing of fracture, without any surgical intervention using systemic recombinant PTH.
Case report A 62-year-old post menopausal female presented in the outpatient department of orthopedics with pain in her right hip and groin which was aggravated upon weight bearing since past 4 weeks. On enquiry, she revealed there was no history of fall or trauma. She was diabetic patients and was on oral hypoglycemic drugs since 3 years. She never smoked cigarettes or drank alcohol. Routine radiographs were within normal limit except for osteopenia. Her BMD measurement was performed and her T score was found to be -6.9. Serum analysis was within normal limits. She was advised bed rest and analgesics but there was no improvement in her symptoms. After 2 weeks an MRI of pelvis with both hips was taken, which showed (Figure 1) the presence of fracture line extending obliquely from superolateral aspect of neck of femur with edema, suggestive of tensile type of stress fracture NOF. Patient was advised strict non weight bearing mobilization and it was decided to give teriparatide subcutaneous injection 20 microgram daily. She was also supplemented with oral Vitamin D (60,000IU/week) and calcium supplement (500 mg b.i.d). Gradually there was improvement in patient’s symptoms. Three months later a repeat MRI (Figures 2, 3) showed complete healing of the fracture line with resolution of the edema.
Discussion Introduction The exuberant information of the literature describing the stress fracture neck of femur (NOF) provides very little information on the treatment for the same in individuals with multiple risk factors for fracture healing. There is no consensus among the orthopedic surgeons to manage these patients. Some surgeons recommend immobilization others recommend prophylactic surgery in the form of screw fixation, but both modalities may result in non union of fracture because of impaired healing. Based on the anabolic effects of teriparatide, there is some evidence for its use in the treatment of fresh fractures and non unions. There is a tremendous research and debate going on as far as teriparatide (recombinant PTH) is concerned in the treat-
210
The first description of femoral neck stress fracture in the literature was published by Asal (1) in the German Arch für Klinische Chirurgie, in 1936. Since that time, numerous articles have recognized these fractures as difficult entities to treat. Stress fractures of the femoral neck are uncommon injuries, comprising group of injuries that result from cyclic mechanical stresses. They occur either as fatigue or insufficiency fractures. Stress fractures around neck of femur are seen in two distinct populations: 1) young, healthy, active individuals who are involved in high demanding activities; and 2) the elderly, who have osteoporosis (2). Fatigue fractures frequently occur because of athletic activities. Competitive runners, ballet dancers and military recruits are classically associated with these types of fractures (3). Elderly individuals are more often Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
13-Meena_- 28/01/14 17:56 Pagina 211
Tensile type of stress fracture neck of femur: role of teriparatide in the process of healing in a high risk patient for impaired healing of fracture
Figure 1 - Plane radiograph of pelvis with bilateral hip showing osteopenia.
Figure 2 - MRI of pelvis with bilateral hip (both T1 & T2 weighted) showing tensile type of fracture with bone edema.
culprits for insufficiency type of stress fractures, which occur during normal activities of daily living. Osteoporosis, osteomalacia, rheumatoid arthritis, diabetes, hyperparathyroidism, scurvy and irradiation all are associated with an increased risk of femoral neck insufficiency fractures (3, 4). First and most commonly used classification system for stress fracture neck of femur was given by Devas (5) in 1965. He classified stress fracture neck of femur into two types that differed radiographically and had diverse clinical progression and outcomes; namely compression and tension type of stress fractures. The compression type of femoral neck stress fracture has radiographic changes in the form of internal callus formation on the inferior femoral neck without apparent cortical disruption; this type of fracture is thought to mechanically stable. The transverse type of femoral neck stress fracture is directed perpendicular to the line of force transmission in the femoral neck, originates at the superior surface of the femoral neck, and results from tension; this type of fracture is inherently unstable and at increased risk for displacement. Magnetic Resonance imaging (MRI) is 100% sensitive, specific and accurate in identifying a femoral neck stress fracture (6). In our patient it was a tensile type of fracture which was diagnosed with MRI. The plain radiographs initially taken failed to detect the fracture. Compression type fractures of the femoral neck are mechanically more stable, so they can be managed with non operative treatment (6). Tension types of stress fractures are potentially unstable and they require with the use of Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
Figure 3 - MRI of pelvis with bilateral hip (both T1 & T2 weighted) showing healing of fracture with resolution of bone edema.
internal fixation (2, 5) in young individual, whereas in elderly individuals surgical option include open reduction internal fixation or prosthetic replacement. Our patient had a classical indication for surgery but surgery was deferred as the patient had all the risk factors which would lead to impaired healing, including old age, estrogen deficiency and diabetes mellitus. The severe osteoporosis itself would not have provided adequate hold of the implant and there may have been a failure of desired function of the implant. So it was decided to manage the patient conservatively with non weight bearing mobilization and teriparatide. To improve the BMD, she was also supplemented with oral Vitamin D (60,000IU/week) and calcium supplement (500 mg b.i.d). We expected that the PTH treatment would provide the necessary stimulus needed to increase the number and quality of osteoblasts and osteoclasts to form basic multicellular units (BMU) at the stress fracture site and bring about the healing. Most complications after femoral neck stress fracture are associated with fracture displacement (7) or delay in diagnosis (8). As tensile type of fractures are highly unstable and is prone to displacement, hence more chances of complication related to fracture displacement (7-9) (osteonecrosis, non union and malunion) than compressive type. There are several conditions that can impair fracture-healing including diabetes, glucocorticoid treatment, osteoporosis, advanced age, and metabolic bone disease (10). Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis (11), and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures. At the time of writing, PTH 1-34 (teriparatide) is the FDA-approved form of PTH for use in treating osteoporosis in humans. While the animal studies performed to date concluded that the systemic PTH treatment can improve healing in advancing age, in ovariectomized rats. The most prominent benefits from PTH would be from its potential use on patients in whom bone repair may be delayed or impaired. Andreassen et al. (12) reported results of a study comparing fracture-healing in two to three-month old rats with aged (twenty-seven-month-old) rats treated with intermittent PTH 1-34 (200 mg/day) or vehicle alone. The study also noted that a reduction in the number of osteoprogenitor cells and/or a diminished rate of maturation of pre-osteoblasts to osteoblasts is correlated with old age. Overall remodelling capacity declined in association with this diminished osteoblastic activity,
211
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R. Malhotra et al. raising the question of whether older animals would respond to PTH as robustly as younger animals. PTH treatment of healing fractures in these older rats led to both increased callus formation and increased mechanical strength by twentyone days after fracture. The ovariectomized rat is a commonly used animal model of osteoporosis in which the operative removal of the ovaries mimics the metabolic condition of loss of estrogen in postmenopausal women. Jahng and Kim (13) have used ovariectomized rats to test the efficacy of PTH in fracture repair in this model of estrogen deficiency. The results of this study demonstrated that an impaired fracture-healing response in the ovariectomized animals, including an inhibition of mineralized bone formation and a reduction of trabecular bone formation at the later stages of repair. Both PTH treatment groups displayed increased callus formation with high-dose PTH, with callus formation approaching that seen in sham-operated control animals in terms of percent of trabecular bone volume in the callus. These results support the conclusion that PTH can act as an anabolic treatment for fracture repair in an ovariectomized model of osteoporosis. The studies (14, 15) on the rat model clearly demonstrate that systemic PTH treatment leads to increased callus volumes, rates of new bone formation, and restoration of mechanical competence in the models of both normal and impaired fracture repair. Considering these teriparatide results in a rat model of long bone fractures and our finding in a severe osteoporotic, postmenopausal woman with stress fracture neck of femur, we think that sufficient information has accumulated that we can safely suggest that teriparatide therapy can be included in a list of possible treatment modalities of adult patients with atypical fractures which are not complete and in high risk individual for fracture healing. Moreover, assuming that our results can be duplicated, we recommend that controlled trials of teriparatide can be conducted to test whether it produces consistent healing of this apparently uncommon fracture in a high risk individual for impaired fracture healing.
212
References 1. 2. 3. 4. 5. 6.
7.
8. 9. 10. 11.
12.
13.
14.
15.
Asal D. Überlastungsschäden am Knochensystem bei Soldaten. Arch für Klinische Chirurgie 1936;186:511-522. Egol KA, Koval K J, Kummer F, et al. Stress Fractures of the Femoral Neck. Clin Orthop Relate Res 1998 Mar;348:72-78. Daffner RH, Pavlov H. Stress fractures: Current concepts. Am J Roentgenol 1992;159:245-252. Tountas AA. Insufficiency stress fractures of the femoral neck in elderly women. Clin Orthop Relate Res 1993;292:202-209. Devas MB. Stress fractures of the femoral neck. J Bone Joint Surg 1965;47B:728-737. Shin AY, Morin WD, Gorman JD, et al. The superiority of magnetic resonance imaging in differentiating the cause of hip pain in endurance athletes. Am J Sports Med 1996;24:168-176. Visuri T, Vara A, Meurman KOM. Displaced stress fractures of the femoral neck in young male adults: A report twelve operative cases. J Trauma 1988;28:1562-1569. Johansson C, Ekenman I, Tornkvist H, et al. Stress fractures of the femoral neck in athletes. Am J Sports Med 1990;18:524-528. Fullerton LR, Snowdy HA. Femoral neck stress fractures. Am J Sports Med 1988;16:365-377. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br 2007;89:1553-1560. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007;146:326-339. Andreassen TT, Fledelius C, Ejersted C, et al. Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 2001;72:304-307. Jahng JS, Kim HW. Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 2000;23:1089-1094. Nakajima A, Shimoji N, Shiomi K, et al. Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34). J Bone Miner Res 2002;17:2038-2047. Nakazawa T, Nakajima A, Shiomi K, et al. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 2005;37:711-719.
Clinical Cases in Mineral and Bone Metabolism 2013; 10(3): 210-212
