|Year : 2022 | Volume
| Issue : 3 | Page : 165-171
Role of teriparatide (rh PTH) in fracture healing of osteoporotic patient
Vinod Kumar1, Jaydeep Patel2, Ashutosh Verma3, Rohit Yadav4, Chandra Prakash Pal5
1 State Medical College Bahraich, Bahraich, India
2 Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
3 Department of Orthopedics, King George Medical University, Lucknow, India
4 Department of Orthopedics, Hind Medical College, Lucknow, India
5 Department of Orthopedics, S.N. Medical College, Agra, Uttar Pradesh, India
|Date of Submission||21-Oct-2022|
|Date of Acceptance||21-Nov-2022|
|Date of Web Publication||15-Dec-2022|
Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Osteoporosis a disease where decreased bone strength increases the risk of a fracture. It is the most common reason for fracture among the elderly. Osteoporosis, an imbalance between bone resorption and bone formation. The diagnosis of osteoporosis can be made using conventional radiography and by measuring the bone mineral density. Osteoporosis is diagnosed when the bone mineral density is less than or equal to 2.5 standard deviations below that of a young reference. Teriparatide, a recombinant form of parathyroid hormone (identical to a portion of human parathyroid hormone (PTH)), intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone turnover. Teriparatide is the only anabolic agent (i.e., bone growing) indicated for use in postmenopausal women with osteoporosis at a high risk for fracture or with a history of osteoporotic fracture, patients with multiple risk factors for fracture. It has been FDA-approved since 2002. Materials and Methods: Over duration of october 2016 to march 2018, 60 patients who have fracture with osteoporosis admitted in S.N. Medical College, Agra. Patient suspected to have osteoporosis based on conventional radiography. Selected patients in the study undergone confirmation of osteoporosis by dual energy absorptiometry and those who are below 2.5 standard deviation are kept in study. Patients fitting into inclusion criteria would form the study group. Data collected by interviews, observation of clinical and radiological findings. 60 patients divided in two groups as cases and controls. Cases are subjected to teriparatide therapy and controls given placebo. Results: Bone formation marker alkaline phosphatase were 150% above baseline after 8 weeks in the teriparatide-treated patient. At 8 weeks, approximately 91.037% in the teriparatide group showed improved healing of osteoporotic fracture compared to 57.14% in the placebo group. Conclusion: Our findings suggest that teriparatide provide selective advantages to fracture healing or functional recovery in the management of osteoporotic fractures. Teriparatide effective in accelerating and increasing the rate of fracture healing. However, more randomized controlled trials are needed to evaluate with certainty the impacts of Teriparatideosteoanabolic role in fracture healing to decide on incorporate this drug as a standard option for conservative management of osteoporotic fracture.
Keywords: Fracture, osteoporosis, PTH
|How to cite this article:|
Kumar V, Patel J, Verma A, Yadav R, Pal CP. Role of teriparatide (rh PTH) in fracture healing of osteoporotic patient. J Bone Joint Dis 2022;37:165-71
|How to cite this URL:|
Kumar V, Patel J, Verma A, Yadav R, Pal CP. Role of teriparatide (rh PTH) in fracture healing of osteoporotic patient. J Bone Joint Dis [serial online] 2022 [cited 2023 Feb 6];37:165-71. Available from: http://www.jbjd.in/text.asp?2022/37/3/165/363856
| Introduction|| |
Osteoporosis is a silently progressive metabolic bone disease that leads to loss of bone mass, is widely prevalent in India and worldwide osteoporotic fractures are a common cause of morbidity and mortality in adult Indian men and women. It is possible that a dietary deficiency of calcium, beginning early in life, it leads to a lower peak bone mass, and consequently osteoporosis at an earlier age. Malabsorption of calcium due to a subclinical deficiency of vitamin D may lead to osteoporosis, without causing osteomalacia. Due to increase in life expectancy, osteoporosis has become a serious public health problem in India and a multidisciplinary approach is needed to identify its aetiological factors and devise strategies for mass prevention of calcium and vitamin D deficiency.
Osteoporosis,,,, a disease where reduced bone strength increases the risk of a fracture. It may be potential reason for fracture among the elderly. It is a serious medical problem and a burden on the healthcare system. Many patients will experience significant functional loss, poor health-related quality of life (HRQoL), and higher mortality rate. Osteoporosis,, an imbalance between bone resorption and bone formation. The diagnosis of osteoporosis, can be made using conventional radiography and by measuring the bone mineral density. Osteoporosis is diagnosed when the bone mineral density is less than or equal to 2.5 standard deviations below that of a young reference.
A bone fracture can be the result of high force impact or stress, or a trivial trauma as a result of certain medical conditions that results in poor bones stock, such as bone cancer, or osteogenesisimperfecta, where the fracture is termed a pathological fracture.
Teriparatide, a recombinant form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, the bioactive portion of the hormone. It is an effective anabolic peptide (i.e., bone growing) used in the treatment of some forms of osteoporosis. Also occasionally used as off-label therapy to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH), intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone turnover.
Teriparatide is the only anabolic agent (i.e., bone growing) indicated for use in postmenopausal women with osteoporosis at a high risk for fracture or with a history of osteoporotic fracture, patients with multiple risk factors for fracture, and for patients who have failed or intolerant to other available osteoporosis therapy. It has been FDA-approved since 2002. It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year) and reducing the risk of fragility fractures.
Endogenous PTH, is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores.,
| Material and Methods|| |
Over duration of october 2016 to march 2018, 60 Patients will be selected from Emergency Department and OPD of Orthopaedics. All cases of fracture with osteoporosis admitted in S.N. Medical College, Agra.
Patient suspected to have osteoporosis based on conventional radiography. The radiographic features of generalized osteoporosis are increased radiolucency and cortical thinning. Increased radiolucency is the result of resorption and thinning of the trabeculae, some of which may be lost. As a consequence, the term osteopenia (“poverty of bone”) is used as a generic term for radiographic signs of decreased bone density. Trabecular bone responds to metabolic changes faster than does cortical bone [Figure 1].
Selected patients in the study undergone confirmation of osteoporosis by dual energy absorptiometry and those who are below 2.5 standard deviation are kept in study.
Patient with age group >40 yrs and osteoporotic (confirmed by DEXA scan below 2.5 standard deviation) with fracture are included. Patient with history of bone tumors, bone cancer, or other cancers that have spread to patient bones, pathological fractures, Stress fracture, open epiphyses,open fracture, history of x-ray radiation therapy, Pregnancy or breast feeding are excluded. Institution of therapy on selected patients with subcutaneous injection of teriparatide 20mcg daily for 28 days of a month upto 6month. Repeat of cycle for next consecutive 3 months.
Site for injection [Figure 2].
During therapy of teriparatide adequate intake of calcium and vitamin D ensured. Patient will be kept in follow-up to lookout for any complication. Patient taught to use drug and care.
All the cases undergoing the procedure at S.N. Medical college will be evaluated using investigations: Serum marker-alkaline phosphatase (bone) and Fracture union is defined as recanalization of the trabeculae or visible bridging callus on both radiograph views; delayed union was defined as no signs of fracture healing for 24 weeks; and nonunion was defined as the absence of bone union 36 weeks postoperatively [Table 1] and [Table 2], [Figure 3].
|Table 1: Bone specific serum alkaline phosphatase. - mcg/lt at base line|
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To address the timing hypothesis (anabolic window) in subjects randomized to teriparatide and placebo, the peak of alkaline phosphatase for each study participant was determined along with the ordering of the peaks. Marker will be analyzed separately. The bone turnover marker was expressed as mean percent changes from baseline. The percent changes in biochemical marker from the average baseline values and the 90% confidence intervals (CI) were calculated.
Comparison of percent change in bone turnover marker between randomized treatment groups was performed using the ANOVA test for continuous variables and ranked-order data or for categorical results. Statistical analysis was done with ANOVA test. Statistical testing was performed at a two-sided significance level of 0.05 unless otherwise noted.
| Observation and Results|| |
Study subjects and baseline characteristics
Data were collected from october 2016 to march 2018, a total of 60 patient were screened. Of the 60 patient, 30 were enrolled as case in the study and 30 patient as control [Table 3]. A total of 30 of the 60 subjects were then randomized into two treatment groups: teriparatide, 20 μg or placebo injections. All participants had normal serum calcium levels for the duration of the study. No serious adverse events were reported. There were nosignificant differences in the baseline characteristics for the two groups.
Some x-ray of osteoporotic patients with fracture fixation and augmented healing with teriparatide therapy
1.70yr old female with fracture shaft tibia treated with intramedullary nail and on teriparatidetherapy, x-ray after 2wk and after 12wk of post-op. [Figure 4] 3.67yr old male with fracture proximal tibia with plate osteosynthesis and on teriparatidetherapy, post-op x-ray after 4wks and 12wks [Figure 5].
|Figure 4: X-ray of patient prior and after use of Teriparatide showing union|
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|Figure 5: X-ray of patient prior and after use of Teriparatide showing union|
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4.80 yr old female with fracture shaft humerus treated with plate osteosynthesis and on teriparatide therapy [Figure 6].
|Figure 6: X-ray of patient prior and after use of Teriparatide showing union|
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5.76yr old male with fracture distal end femur treated with plate osteosynthesis and patella encirclage and on teriparatidetherapy, pre-op and post-op x-ray afer 4wks and 8wks [Figure 7].
|Figure 7: X-ray of patient prior and after use of Teriparatide showing union|
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| Discussion|| |
The present study was conducted on 60 patients divided in two groups as cases and controls. Cases are subjected to teriparatide therapy and controls given placebo. This prospective, placebo-controlled study was designed to determine whether daily teriparatide treatment increased bone formation marker (alkaline phosphatase) in fracture healing in osteoporotic fracture [Table 1] and [Table 2], [Figure 3].
This pilot study did not demonstrate definitively that teriparatide versus placebo resulted in accelerated healing of osteoportic fractures/injuries over 8 weeks. Although not significant, our results suggest that a larger percent of osteoporotic fractures showed some improvement or healing of their fractures in the teriparatide versus placebo-treated subjects, which warrants further study in a larger clinical trial.
Our results showed that bone formation marker alkaline phosphatase significantly increased over 8 weeks of daily administration of teriparatide. These rises in alkaline phosphatase stimulation of bone formation activity, which supports the evidence that intermittent PTH has an anabolic effects on bone in osteoprotic fractures (Glover et al., 2009; Goltzman, 2008;).,
In premenopausal women with lower extremity stress fractures treated with teriparatide but not placebo, bone formation markers ALP, P1NP and OC increased rapidly at 4 weeks by150%, 133.58% and 409.60%, respectively. This early increase in bone formation markers in teriparatide-treated women with stress fractures is similar to previous findings in postmenopausal women with osteopenia (Glover et al., 2009).
These findings suggest enhanced anabolic activity, which has been associated with increased BMD and enhanced bone strength in postmenopausal women (Chen et al., 2007; Hodsman, Fraher, Ostbye, Adachi, and Steer, 1993)., In premenopausal women, treated with teriparatide (20 μg), high levels of bone formation marker P1NP correlated with an improvement in spine and hip BMD (Langdahl et al., 2009).
Nevertheless, bone formation marker alkaline phosphatase were 150% above baseline after 8 weeks in the teriparatide-treated patient and statistically significant at all timepoints. These results support previous findings that ALP,P1NP and OC indicate increases in bone formation during daily teriparatide therapy.
This rise in bone turnover marker reflects acceleration in bone turnover, which if the net effect is bone formation, results in increased total skeletal mass (Lindsay et al., 1997; McClung et al., 2005).,
Although teriparatide has shown an effect on overall bone remodeling, there was no significant evidence on bone resorption markers examined in our study (Glover et al., 2009). This lack of response may be due to the study design than the efficacy of teriparatide.
Typically, response in resorption markers to teriparatide treatment peak at six months (Lindsay et al., 1997). Since our study was designed to test the effects of teriparatide on bone healing in a two month interval, significant associations with teriparatide and markers of bone resorption were not observed as anticipated.
Though not conclusive, it appears that teriparatide increased the number of healed participants compared to placebo. At 8 weeks, approximately 91.037% in the teriparatide group showed improved healing of osteoporotic fracture compared to 57.14% in the placebo group, though results were found not significant (P = 0.31). In twelve participants treated with placebo, three participants (25%) showed no change, while only one out of twelve (8.33%) participants in the teriparatide treated group was unresponsive to treatment.
Another important factor to considerd is the location of the osteoporotic fracture. Each bone has a different biological and mechanical property that affect the healing of bone (whitefield, 2002).
Our results differed from a placebo-controlled trial in osteoporotic patient treated with teriparatide, in whom NTX levels remained elevated until 6 months and then declined towards baseline at 11 months (E. S. Orwoll et al., 2003).
The immediate robust response to markers of bone formation as early as 4 weeks followed by a delayed response in bone resorption reflects the anabolic window as described by Rubin and Bilezikian (Bilezikian, 2008; Rubin andBilezikian, 2003).
A previous study showed significant increases in CTX concentration after six months of daily teriparatide in premenopausal women (Langdahl et al., 2009). As for NTX, the concentration of this bone resorption marker peaked as early as one month.
Previous studies showed that administration of daily teriparatide increases bone formation and improves bone microarchitecture and structure that may be helpful during bone repair (Dempster et al., 2001; Jobke et al., 2011).,
At present there are few randomized placebo-controlled studies of the effects of PTH on healing of fracture (Aspenberg et al., 2010; Peichl et al., 2011).,
In the only placebo-controlled trial studying the effects of teriparatide on fracture repair, distal radius fractures in postmenopausal women were observed and had showed an acceleration of fracture repair in those treated with teriparatide (20 μg) than placebo or teriparatide (40 μg) (Aspenberg et al., 2010).
Because of these anabolic effects, daily administration of teriparatide is being experimentally used in non-controlled study to assist healing in delayed or non-union fractures.
In a case study, daily teriparatide (20 μg) was used in a postmenopausal woman with a femoral fracture that showed no healing after a year. After treatment, patient showed radiographic closure of the fracture in one month and increased levels of ALP,OC and CTX in three months (150%, 300 and 22%, respectively) (Carvalho, Voss, Almeida, Salgado, and Bandeira, 2011).
Following a prospective study in fourteen patients with atypical femoral fractures, five patients that received teriparatide showed a significant increase in ALP, P1NP and CTX (150%, 343 and 196%, respectively) as well as a complete union fracture in two patients. By comparison, only one fracture healed in those who did not receive teriparatide (Chiang et al., 2013). In our placebo-controlled study, a significant rise in bone formation markers was observed. This rapid response in bone formation markers suggest stimulated bone remodeling, which has been associated with increase remodeling sites of bone formation after administration of teriparatide (Ma et al., 2006).
Aspenberg et al. randomized trial controlled this confounding effect and only studied fractures of the distal radius in postmenopausal women (Aspenberg et al., 2010). Currently, there are no longitudinal studies that examine the effects of teriparatide and fracture healing in premenopausal women.
Our study has some limitations. One primary limitation was the sample size of this pilot study. Despite extensive recruitment efforts, enrollment of study participants within acute onset of osteoporotic injury was a challenge. Recruitment efforts were directed at working with several orthopedic surgeons, physiatrists. Another limitation of this study is that teriparatide is currently only FDA approved as a daily injection. Thus, participation in this study required that self-administer the teriparatide as a daily injection, which was a deterrent for some patient (Shiraki et al., 2013). Thus, this small sample size may have led to increased variability in bone biomarker responses and limited the power to demonstrate a significant acceleration of bone healing in response to teriparatide versus placebo. That being said, the results from this pilot study demonstrate an anabolic window in teriparatide- but not placebo-treated osteoporotic fractures that holds promise for future larger scale, placebo-controlled studies of the effects of teriparatide on bone healing.
| Summary and Conclusion|| |
Teriparatide constitutes the active portion of the Parathyroid Hormone molecule and is a commercially available, Food and Drug Administration (FDA) approved agent for the treatment of Osteoporosis. Emerging research over the last decade has shown a potential application in fracture management. Widespread evidence obtained from studies utilising of animal models indicate Teriparatide may improve fracture healing. Significant improvements in callus volume, callus mineralisation, bone mineral content, strength and rate of successful union at the fracture site in both normal and delayed healing models has been demonstrated. Research in humans is relatively less with only two randomised controlled trials have till date. However the results of the human studies are in line with their animal counterparts and it seems that inferences can therefore be made despite obvious differences in PTH metabolism between the species.
Teriparatide is being used “off license” for the management of fractures and non-unions by physicians who are confident of its beneficial effect. Randomised controlled trials are required for thorough analysis of the actions of Teriparatide in human subjects (in both normal and delayed healing models). This may give conclusive decisions to be made on whether or not to install this product as a standard option for conservative management of fractures and non-unions.
There is no reason to disbelieve the efficacy of teriparatide in improving functional outcome and inducing fracture healing in the osteoporotic patient.
This study favors that teriparatide provide selective advantages to fracture healing of and recovery in the treatment of osteoporotic fractures. The role of teriparatide on osteoporotic fractures requires evidences from large scale prospective randomized trials.
In summary, widespread evidence acquired from studies with animals and human show that Teriparatide improves and may accelerate fracture healing in osteoprotic. Nevertheless, results from human studies suggest that it may be effective in accelerating and increasing the rate of fracture healing.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]