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. 2021 Feb 7;17:54–58. doi: 10.1016/j.jcot.2021.01.019

Present and future scope of recombinant parathyroid hormone therapy in orthopaedics

Arnab Sain 1, Hemant Bansal 1,∗, Kirubakaran Pattabiraman 1, Vijay Sharma 1
PMCID: PMC7920101  PMID: 33717971

Abstract

Parathyroid Hormone (PTH) has a significant role in calcium metabolism. Its intermittent administration has an anabolic effect on bone mineralization. Teriparatide (PTH 1-34), a recombinant form of parathyroid hormone, is useful in the treatment of osteoporosis, fracture healing, non-union, stress fracture, augmentation of implant fixation with bone, and chondroprotection in osteoarthritis. The present review article will elaborate on the potential approved uses of recombinant PTH in orthopedics and its evolving role in the management of fracture osteosynthesis and other common challenging bone pathologies.

Keywords: Parathyroid hormone (PTH), Teriparatide, Osteoporosis, Fracture healing, Stress fracture, Osteonecrosis

1. Introduction

Parathyroid hormone (PTH) is a naturally produced hormone by the parathyroid glands of the human body. It has a vital role in calcium metabolism and is involved in the release of calcium from the bones to maintain serum calcium concentration. However, the intermittent parathyroid hormone has an anabolic effect on bones thus, has a role in the treatment of Osteoporosis, fracture healing, non-union, stress fracture, and also improves fixation of the implant to bone.1 Natural occurring parathyroid hormone consists of 84 amino acids. Teriparatide (PTH 1-34) is a recombinant form of parathyroid hormone, consisting of the first 34 amino acids. It retains all of the biologic activity of the intact peptide.1, 2, 3

Recombinant parathyroid hormone has been used extensively in the last decade, especially for the management of osteoporosis. Its anabolic effect on bones has allowed its potential use in the management of other imperative aspects of orthopedics such as fracture healing, fixation augmentation, osteonecrosis, etc. However, its varied application in orthopedics lacks significant scientific evidence and is under research. There is also contentious opinion on the doses and duration of the PTH therapy and to the best of our knowledge, there is no comprehensive literature available highlighting the current and future application of PTH in orthopedics. Thus, this article has reviewed the present application of recombinant PTH in orthopedics and its possible evolving application in fracture management.

2. Methodology

PubMed, EMBASE, and Cochrane registry searches were performed using the keywords “parathyroid hormone,” “osteoporosis”, “fracture healing”, “non-union”, “osteonecrosis”, “chondroprotection”, “Augmentation of implant fixation” and “intermittent administration” from 1960 to January 2020. Only articles relating to the role of PTH in orthopedics were selected. Articles related to the role of PTH outside orthopedics and articles related to these pathologies without any reference to PTH were excluded. The Abstracts and the full text of the matched articles were collected and reviewed in detail. References cited in the identified articles were also screened for inclusion. A total of 46 articles related to the present study objectives were included and reviewed extensively to consider the therapeutic potential of PTH administration in orthopedics.

3. Uses

3.1. Treatment of osteoporosis

Osteoporosis is a state of the bone characterized by low bone mass associated with structural deterioration of bone architecture and increased risk of fragility fractures. The prevalence of osteoporosis is increasing and now it is an important health problem of the aged population. Most of the treatment options for osteoporosis (e.g., Estrogen, Bisphosphonates, Calcitonin, and Selective Estrogen Receptor Modulators) are anti-resorptive agents that act on osteoclasts to prevent further bone loss. When delivered intermittently at low doses PTH potentially stimulates cortical and trabecular bone growth.2 Teriparatide (PTH 1-34), a recombinant form of parathyroid hormone is used worldwide for the treatment of osteoporosis in postmenopausal women with a high risk for fracture and also for the treatment of osteoporosis in men.3

3.1.1. Effect of PTH on osteoporosis in postmenopausal women

Treatment of postmenopausal osteoporosis with Teriparatide decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density.4 The 40-μg dose showed a higher increase in bone mineral density more than the 20-μg dose but in long term had similar effects on the risk of fracture and had higher chances of having side effects [4]. PTH (1-34) significantly increases bone mineral density (BMD) at all skeletal sites except the radius and significantly reduces the risk of new vertebral and nonvertebral fractures in postmenopausal women with prior fractures.5 Hodsman et al.6 used PTH (1-84) for the treatment of postmenopausal osteoporosis and found it to be effective in improving BMD with the associated risk of hypercalcemia (Table 1). The duration of therapy with PTH should be limited to 2 years as there is evidence of the development of osteosarcoma in rat models.7 The calcium supplementation should be restricted to 1500 mg and Vitamin D supplementation limited to 1000 IU.8

Table 1.

Studies showing the effect of PTH on post-menopausal osteoporosis.

Study Methods Results
Neer et al.4 20 μg and 40 μg dose of PTH (1-34) for mean duration of 21 months in post-menopausal women once daily subcutaneous 40 μg dose once daily subcutaneous dose of PTH (1-34) more effective in BMD by DEXA but had similar effects on fracture risk and had more chance of side effects.
Hodsman et al.6 50,75 &100 μg of PTH (1-84) daily subcutaneous injection vs placebo in post-menopausal women for 12 months 100 μg increased BMD significantly at 3 months (+2%) and 12 months (+7.8%) but had incidence of hypercalcemia.
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3.1.2. Effect of PTH on osteoporosis in men

PTH (1-34) treatment increases bone mineral density and is a potentially useful therapy for osteoporosis in men.9,10 Biochemical markers of bone formation and Spine bone mineral density, femoral neck bone density increased with Teriparatide therapy10 (Table 2).

Table 2.

Studies showing effect of PTH on osteoporosis in men with dosage used and results.

Study Methods Results
Kurtland et al.9 25 μg of PTH (1-34) vs. placebo for 18 months PTH group had an increase in lumbar spine bone mass by 13.5%.
There was no change in radial bone mineral density.
Orwoll et al.10 20 μg, 40 μg of PTH (1-34) vs. placebo for 11 months PTH increased spine and femoral neck BMD.
40 μg dose had increased side effects. No effect of PTH on distal radius bone density.
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3.1.3. Effect of PTH in combination with hormone replacement therapy

PTH has an increased anabolic effect on the axial skeleton in patients on hormone-replacement therapy (HRT). PTH also increases the bone mineral content, without any detrimental effects at any skeletal site. The increased vertebral mass was associated with a reduced rate of vertebral fracture, despite increased bone turnover.11,12 Table 3, summarizes the studies on the combined effect of HRT and PTH along with the dose of PTH used.

Table 3.

Studies showing the efficacy of the combined effect of HRT and PTH on postmenopausal osteoporosis.

Study Methods Results
Cosman et al.11 27 Women on HRT were given 25 μg of PTH (1-34) daily subcutaneous for 3 years vs. 25 women on HRT alone. PTH (1-34) in addition to HRT effectively increased BMD and decreased the incidence of vertebral fractures.
Lindsay et al.12 17 women on HRT were given 25 μg of PTH (1-34) for 3 years vs. 17 women on HRT alone. PTH (1-34) increased vertebral bone mass and reduced incidence of vertebral fractures.
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3.1.4. Effect of PTH in combination with alendronate

Sequential treatment of osteoporosis with PTH and alendronate results in an increase in vertebral bone density that is considerably more than has been reported with alendronate or estrogens alone. This combination of drugs may be a useful approach to maximizing bone density in women with vertebral osteoporosis.13 However, there was no evidence of synergy between parathyroid hormone and alendronate given in combination at the same time. The concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone.14 Also, one study showed that after one year of parathyroid hormone therapy, an increase in bone density was maintained or increased with alendronate but lost if the parathyroid hormone is not followed by an antiresorptive agent.15 Table 4, summarizes the studies on the combined effect of PTH and Bisphosphonates.

Table 4.

Studies showing the efficacy of the combined effect of PTH and Bisphosphonates on postmenopausal osteoporosis.

Study Methods Results
Rittmaster et al.13 66 post-menopausal women treated with 50.75,100 μg of PTH (1-84) for 1 year followed by daily treatment of Alendronate 10 mg daily for another 1 year. PTH (1-84) followed by alendronate resulted in an increase in vertebral BMD.
Black et al.14 238 post-menopausal women were given daily treatment with only PTH (1-84) 100 μg (119 women), Alendronate 10 mg (60 women) or both (59 women) and followed for 12 months. Alendronate given simultaneously with PTH reduced the anabolic effect of PTH.
Black et at15 Women who had received 100 μg of PTH (1-84) for 1 year were given either Alendronate 10 mg daily or Placebo and followed for 1 year. The BMD increase achieved by PTH (1-84) was maintained in women given alendronate therapy.
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Teriparatide PTH (1-34) is now approved for the treatment of osteoporosis in 20 μg daily subcutaneous injection for 18 months and never more than 24 months.16,17

3.1.5. Newer analogs

Abaloparatide is a new pharmacological option for osteoporosis, particularly in postmenopausal women. It is a parathyroid hormone-related protein analog that acts as an agonist at the PTH1 receptor. It results in a greater increase in bone mineral density and less hypercalcemia compared to Teriparatide.18

3.2. Enhancement of fracture healing

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired fracture healing is common in certain risk groups, such as the elderly, osteoporosis, malnutrition, and women after menopause.19

Several animal studies suggest that PTH could be beneficial in the treatment of fractures.19 Also, fractures in animals with experimental conditions such as aging, Estrogen withdrawal, and malnutrition showed faster healing after PTH treatment.19 Some studies showed that intermittent PTH administration increased callus volume and bone mineral content of callous in rat bone fractures.20,21

In a randomized control study in humans, it was found that 20 μg of teriparatide reduced the time needed for fracture healing as compared to 40 μg and placebo.22 However, there is no clear agreement in this regard. A meta-analysis of 8 RCTs by Hong et al.,23 suggested that significant improvement was present in patients who received PTH concerning fracture healing time, pain relief, and functional outcome. But no significant differences were seen in the fracture healing rate or adverse events like light-headedness, hypercalcemia, nausea, sweating, and headache, except for slight bruising at the injection site. The meta-analysis study suggested that PTH is safe and effective in fracture healing.

Shi et al.24 suggested in their meta-analysis that PTH therapy had significant effectiveness with regards to function improvement in patients following the fracture. But there was no significant effect of PTH therapy with regards to the time of radiographic fracture healing, fracture healing rate, and reduction in pain.24

3.2.1. Effect of PTH on hip and pelvic fractures

In osteoporotic trochanteric fractures, Teriparatide resulted in a shorter time for fracture union, better functional outcomes, and less mortality.25,26 A study by Singhal et al.,27 the use of teriparatide in the post-operative period for 6 months in patients with intertrochanteric fractures resulted in faster healing of fracture by 4 weeks and better mobility. In osteoporotic pubic fractures, teriparatide accelerated fracture healing and improved functional outcomes.28 However, in a randomized control study by Bhandari et al.29 on the use of teriparatide in femoral neck fractures, there was no reduction in the risk of revision surgery. Also, it did not improve fracture healing or decrease pain and did not improve functional outcome in the postoperative period.29

3.2.2. Effect of PTH on fractures of the upper extremity

In a prospective RCT by Aspenberg et al.,30 Teriparatide (20 μg) reduced fracture healing time in osteoporotic fractures of the distal radius in postmenopausal women. Also, teriparatide increased callus formation in distal radius fractures.30 However, in proximal humerus fractures, Teriparatide did not affect bone healing or functional outcomes.31

3.2.3. Effect of PTH on vertebral fractures

Iwata et al.32 suggested that teriparatide enhanced fracture healing and improved union rates in osteoporotic vertebral fractures. However, Kang et al.33 found that three-month therapy with teriparatide did not show any protective effect on the progression of fractured vertebra body collapse or kyphosis in patients with osteoporosis. Table 5, summarizes the various studies on the effect of PTH on fracture healing.

Table 5.

Studies showing the effect of PTH on fracture healing.

Study Methods Results
Kim et al.26 Post-operative Inter-trochanteric hip fracture patients treated with daily 20 μg subcutaneous dose of PTH (1-34) for 2 months vs without PTH Shorter time to fracture union and better post-operative functional outcome.
Singhalet al27 Post-operative Inter-trochanteric hip fracture patients treated with daily 20 μg PTH (1-34) subcutaneous dose for 6 months vs without PTH Shorter time to fracture union and better post-operative functional outcome.
Bhandariet al29 Post-operative fracture Neck of Femur treated by PTH (1-34) 20 μg for 6 months vs without PTH No effect on fracture healing or post-operative functional outcome.
Peichl et al.28 Elderly pubic fracture patients given 100 μg of PTH (1-84) vs without PTH Reduced fracture healing time and better functional outcome
Aspenberg et al.30 Distal radius fracture treated by daily low dose (20 μg) and high dose (40 μg) of Teriparatide for 5 weeks PTH (1-34) 20 μg daily increased callus formation and reduced fracture healing time with minimal side effects.
Johansson et at31 Post-menopausal women with proximal humerus fractures managed with daily dose of 20 μg of PTH (1-34) for 4 weeks vs without PTH No effect on fracture healing or clinical outcome.
Iwata et al.32 Osteoporotic vertebral compression fracture treated with daily 20 μg PTH (1-34) vs weekly 35 mg alendronate PTH (1-34) group had reduced fracture union time than alendronate group.
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3.3. Treatment of non-union

There is evidence of the beneficial effect of PTH in delayed union and non-union of fracture in animal and human studies. Lin et al.34 demonstrated that the daily administration of PTH in atrophic non-union increased union rates in mouse models. Another study by Kastirr et al.35 found that PTH had a stimulatory effect on osteoblasts and osteoclasts and definitive healing of aseptic non-unions was found in 95% cases treated with PTH.

The systematic review by Canintika et al.36 suggested that daily subcutaneous injection of teriparatide 20 μg is a potential new safe treatment for delayed union and non-union with no side effects. Oteo-Álvaro et al.37 reported the healing of a non-union of the humerus after 4 months of treatment with teriparatide 20 μg daily subcutaneous dose.

3.4. Augmentation of implant fixation with bone

Intermittent administration of parathyroid hormone (PTH) has an anabolic effect on bone and may improve fixation of the implant to bone particularly arthroplasty implants. Daugaard et al.38 studied the effect of PTH on implant fixation to bone. In one study on the effect of PTH and allograft in arthroplasty implants, it was found that PTH improves bone formation in morselized allograft around implant retains graft volume. However, in this study fixation of implant neither improved nor decreased.38 In another study by Daugaard et al.39 in canine models, found that PTH enhances early fixation of implants surrounded by bone gap by an increase in bone formation in the gap, thus enhancing implant stability. Intermittent PTH administration improved osteointegration in press-fit inserted implants.40 Also, in another study by Oteo-Álvaro et al.,41 PTH improved osteointegration of a hip prosthesis with signs of aseptic loosening. The dose used was 20 μg daily subcutaneous injection of PTH (1-34). So, PTH is useful in improving the osseointegration of implants in challenging situations where bone gap exits around the implant.39,40

3.5. Treatment of stress fractures

PTH has also been shown to be beneficial in stress fractures. Almirol et al.,42 in their study, showed that short-term administration of PTH (1-34) in the dose of daily subcutaneous injection of 20 μg for 8 weeks was beneficial for the healing of lower limb stress fractures as evidenced by increased bone biomarkers and increased cortical thickness.

3.6. Treatment of avascular necrosis of the femoral head

Intermittent PTH has an anabolic effect and leads to bone formation. PTH can be useful for this reason in osteonecrosis of the femoral head as it can lead to bone formation and prevent the collapse of the femoral head. In rat models with vascular deprivation-induced osteonecrosis of the femoral head, PTH had beneficial effects like decreased bone resorption and stimulation of osteogenesis. Also, high dose intermittent injections had better results.43 Another study showed that PTH leads to increased efficacy of core decompression in steroid-induced osteonecrosis by increased osteogenesis and neovascularization.44 Arai et al.45 showed that PTH (1-34) in a daily subcutaneous dose of 20 μg was more efficacious than alendronate 35 mg weekly dose in non-traumatic femoral head osteonecrosis.

3.7. Role in chondroprotection

Sampson et al.46 demonstrated in the mouse model that PTH (1-34) was useful for decelerating cartilage degeneration and inducing matrix regeneration in patients with osteoarthritis. Thus, this opens up a potential beneficial use of PTH (1-34) as a chondroprotective agent and as a disease-modifying therapy in osteoarthritis but human studies are yet to prove it.

4. Approved dosage and contraindications

PTH (1-34) in the name of teriparatide is available worldwide while PTH (1-84) is approved for use only in the European Union. PTH (1-34) is now approved for the treatment of osteoporosis in 20 μg daily subcutaneous injection for 18 months and never more than 24 months.

Absolute contraindications include primary and tertiary hyperparathyroidism, elevated alkaline phosphatase of uncertain cause, Paget’s disease, open epiphysis in children, osteosarcoma, pregnancy, lactation, end-organ failure, metastatic skeletal malignancy, and prior skeletal irradiation.16,17

5. Conclusion

PTH has proved to be beneficial in osteoporosis, fracture healing, non-union, augmentation of fixation of the implant to the bone, stress fractures and osteonecrosis, and osteoarthritis. Although it has definite evidence in osteoporosis, more studies are required to prove its efficacy in fracture healing, non-union, augmentation of implant fixation, stress fractures and osteonecrosis, and osteoarthritis. Also, there is no clear consensus regarding the dosage and duration of PTH administration, therefore more human studies with a larger number of patients are required to prove its efficacy in these situations.

Funding

No funding or grants were received or will be received from any commercial party relating to the subject of this article.

Ethical approval

Ethical approval not required as per our Institute Review Board. All procedures performed in this study involving human participants were in accordance with the ethical standard of the institutional and/international research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Declaration of competing interest

All authors declare that there is no conflict of interest to disclose.

Acknowledgment

None.

Contributor Information

Arnab Sain, Email: arnabsain88@gmail.com.

Hemant Bansal, Email: hemant.21bansal@gmail.com.

Kirubakaran Pattabiraman, Email: kiru2209@gmail.com.

Vijay Sharma, Email: drvijaysharmatrauma@gmail.com.

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