PTH(1‐34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats

Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH_(1–34)) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH_(1–34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647‐labelled pamidronate (Pam) and radiolabeled ¹⁴C‐ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 μg/kg/d PTH_(1–34), and the effects on BP liberation and bone healing were examined by X‐ray, micro‐CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH_(1–34), there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for ¹⁴C‐ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus‐bound BP with PTH_(1–34), these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH_(1–34) increases bone turnover as well as BP turnover. © 2015 American Society for Bone and Mineral Research.     

Safety and Efficacy of PTH 1-34 and 1-84 Therapy in Chronic Hypoparathyroidism: A Meta-Analysis of Prospective Trials

Hypoparathyroidism is the only endocrine deficiency for which hormone replacement therapy is not the standard of care. Although conventional treatments may control hypocalcaemia, other complications such as hyperphosphatemia, kidney stones, peripheral calcifications, and bone disease remain unmet needs. This meta-analysis (PROSPERO registration number CRD42019126881) aims to evaluate and compare the efficacy and safety of PTH₁₋₃₄ and PTH₁₋₈₄ in restoring calcium metabolism in chronic hypoparathyroidism. EMBASE, PubMed, and CENTRAL databases were searched for randomized clinical trials or prospective studies published between January 1996 and March 2021. English-language trials reporting data on replacement with PTH₁₋₃₄ or PTH₁₋₈₄ in chronic hypoparathyroidism were selected. Three authors extracted outcomes, one author performed quality control, all assessed the risk of biases. Overall, data from 25 studies on 588 patients were analyzed. PTH therapy had a neutral effect on calcium levels, while lowering serum phosphate (−0.21 mmol/L; 95% confidence interval [CI], −0.31 to −0.11 mmol/L; p < 0.001) and urinary calcium excretion (−1.21 mmol/24 h; 95% CI, −2.03 to −0.41 mmol/24 h; p = 0.003). Calcium phosphate product decreased under PTH₁₋₈₄ therapy only. Both treatments enabled a significant reduction in calcium and calcitriol supplementation. PTH therapy increased bone turnover markers and lumbar spine mineral density. Quality of life improved and there was no difference in the safety profile between PTH and conventionally treated patients. Results for most outcomes were similar for the two treatments. Limitations of the study included considerable population overlap between the reports, incomplete data, and heterogeneity in the protocol design. In conclusion, the meta-analysis of data from the largest collection to date of hypoparathyroid patients shows that PTH therapy is safe, well-tolerated, and effective in normalizing serum phosphate and urinary calcium excretion, as well as enabling a reduction in calcium and vitamin D use and improving quality of life. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Endogenous parathyroid hormone–related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation

To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8‐week‐old wild‐type and parathyroid hormone–null (PTH^?/?) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase‐positive areas, type I collagen‐positive areas, PTH receptor–positive areas, calcium sensing receptor–positive areas, and expression of bone formation–related genes were all decreased significantly in the diaphyseal regions of bones of PTH^?/? mice compared to wild‐type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH^?/? mice. At 5 days after BMX, active tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts had appeared in wild‐type mice but were undetectable in PTH^?/? mice, Both the ratio of mRNA levels of receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP‐positive osteoclast surface were still reduced in PTH^?/? mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone–related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH^?/? mice. To determine whether the increased newly formed bones in PTH^?/? mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH^?/?PTHrP^+/? mice were generated and newly formed bone tissue was compared in these mice with PTH^?/? and wild‐type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH^?/?PTHrP^+/? mice compared to PTH^?/? mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHrP in osteogenic cells compensates by increasing bone accrual. © 2013 American Society for Bone and Mineral Research     

Delayed short‐course treatment with teriparatide (PTH1–34) improves femoral allograft healing by enhancing intramembranous bone formation at the graft–host junction

Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH_1–34) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40 µg/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40 µg/kg) of PTH_1–34 demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH_1–34 treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2‐week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTH_1–34 were enhanced intramembranous bone formation and remodeling at the graft–host junction. These findings support the potential use of PTH_1–34 as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation. © 2012 American Society for Bone and Mineral Research     

Prolonged Pharmacokinetic and Pharmacodynamic Actions of a Pegylated Parathyroid Hormone (1‐34) Peptide Fragment

Polyethylene glycol (PEG) addition can prolong the pharmacokinetic and pharmacodynamic actions of a bioactive peptide in vivo, in part by impeding rates of glomerular filtration. For parathyroid hormone (PTH) peptides, pegylation could help in exploring the actions of the hormone in the kidney; e.g., in dissecting the relative roles that filtered versus blood‐borne PTH play in regulating phosphate transport. It could also lead to potential alternate forms of treatment for hypoparathyroidism. We thus synthesized the fluorescent pegylated PTH derivative [Lys¹³(tetramethylrhodamine {TMR}), Cys³⁵(PEG‐20,000 Da)]PTH(1‐35) (PEG‐PTH^TMR) and its non‐pegylated counterpart [Lys¹³(TMR), Cys³⁵]PTH(1‐35) (PTH^TMR) and assessed their properties in cells and in mice. In PTHR1‐expressing HEK‐293 cells, PEG‐PTH^TMR and PTH^TMR exhibited similar potencies for inducing cAMP signaling, whereas when injected into mice, the pegylated analog persisted much longer in the circulation (>24 hours versus ～ 1 hour) and induced markedly more prolonged calcemic and phosphaturic responses than did the non‐pegylated control. Fluorescence microscopy analysis of kidney sections obtained from the injected mice revealed much less PEG‐PTH^TMR than PTH^TMR on the luminal brush‐border surfaces of renal proximal tubule cells (PTCs), on which PTH regulates phosphate transporter function, whereas immunostained phosphorylated PKA substrate, a marker of cAMP signaling, was increased to similar extents for the two ligands and for each, was localized to the basolateral portion of the PTCs. Pegylation of a bioactive PTH peptide thus led to prolonged pharmacokinetic/pharmacodynamic properties in vivo, as well as to new in vivo data that support a prominent role for PTH action at basolateral surfaces of renal proximal tubule cells. © 2016 American Society for Bone and Mineral Research.     

Parathyroid cysts of the neck and mediastinum. Case report

Five cases of parathyroid cyst are presented and the literature concerning this rare entity is reviewed. Three of the five cysts were located in the neck and were non-functioning. The other two were in the anterior mediastinum and functioning, and indeed were associated with hypercalcemic crisis. Four cases were treated surgically, and in one non-functioning parathyroid cyst both diagnosis and treatment were accomplished with fine-needle aspiration. The cystic appearance, color of the fluid contents, high content of parathyroid hormone and histologic features distinguish parathyroid cyst from the much commoner thyroid cyst. Non-functioning parathyroid cysts can be treated with fine-needle aspiration, whereas functioning cysts require surgical removal.     

Longitudinal morphological change of acetabular subchondral bone cyst after total hip arthroplasty in developmental dysplasia of the hip

Purpose

The purpose of this study is to clarify morphological changes of acetabular subchondral bone cyst after total hip arthroplasty for osteoarthritis secondary to developmental dysplasia of the hip.

Methods

Two hundred and sixty-one primary cementless total hip arthroplasties of 208 patients, 18 males, 190 females, were retrospectively reviewed. Morphological changes of subchondral bone cyst were evaluated by computed tomography (CT). The mean cross-sectional area of the cyst from CT scans at 3 months postoperatively and after 7–10 years (average 8.4 years) were compared.

Results

Acetabular subchondral bone cysts were found in 49.0% of all cases in preoperative CT scans. There was no cyst which was newly recognized in CT scan performed after postoperative 7–10 years. All the cross-sectional areas of the cysts evaluated in this study were reduced postoperatively.

Conclusions

This study revealed that acetabular subchondral bone cysts do not increase or expand after total hip arthroplasty and indicated that the longitudinal morphological change of acetabular bone cysts in patients of developmental dysplasia of the hip do not influence long-term implant fixation in total hip arthroplasty.

     

Treatment of a Unicameral Bone Cyst of Calcaneus with Endoscopic Curettage and Percutaneous Filling with Corticocancellous Allograft

The surgical procedures for unicameral solitary calcaneal bone cysts have ranged from simple curettage and grafting to subperiosteal resection with internal fixation and grafting. In this article, an endoscopically assisted technique is proposed for the curettage of a simple calcaneal cyst that takes advantage of direct visualization of the cyst wall and contents and permits accurate assessment of the extent of the lesion. After curettage, percutaneous filling of the defect with corticocancellous allograft makes the technique a complete, minimally invasive surgical approach for this condition. The technique uses 2 lateral portals, one for viewing and the other for manipulation, both of which are created under fluoroscopic control. Once the cyst has been located, the 30° arthroscope is used to evacuate fluid, after which more solid cyst contents are fragmented and removed. Thereafter, curettage of the inner surface of the cavernous cyst wall is performed. Finally, complete packing of the previously cystic cavity with crushed corticocancellous allograft is performed under endoscopic visualization and confirmed radiographically.     

Unicameral and aneurysmal bone cysts

One hundred and seventy-eight cases of unicameral bone cysts (UBC) treated with curettage and bone grafting were compared to 141 cases treated with cortisone injections. The end results were comparable in the two groups. Local recurrence risk factors in the surgical group were active cyst and previous operations. In the other group they were multilocation of the cyst, active cyst, and size of cyst. A new radiographic classification of aneurysmal bone cyst (ABC) is proposed in a report of 198 cases of ABC. The treatment of choice in ABC is surgical and the type (curettage, curettage plus phenole or cryosurgery, resection or hemiresection) is selected on the basis of the radiographic aspect and the rate of growth of the cyst. Radiotherapy is only indicated in inoperable ABC cases.     

Your diagnosis? Aneurysmal bone cyst

The etiology of aneurysmal bone cysts is uncertain, but they may originate as a localized arteriovenous malformation. These benign lesions can be primary or occur secondary to an underlying lesion. The majority of patients who present with aneurysmal bone cysts are younger than age 20 years. One half of lesions occur within the long bones and one third involve the spine. Most flat bone lesions, approximately 10%, occur in the pelvis. Fluid-fluid levels are common on CT and MRI but are not pathognomonic. Although aneurysmal bone cyst is benign, there may be aggressive clinical and imaging features. Treatment for aneurysmal bone cyst is surgical curettage, intraoperative adjuvant therapy, and bone grafting of the lesion. The prognosis following treatment is very good, although 10% to 20% of cases are reported to recur.     

The cause of subchondral bone cysts in osteoarthrosis: a finite element analysis

BACKGROUND: The etiology of subchondral bone cysts in arthrotic joints is unclear. MATERIALS AND METHODS: We used two-dimensional finite element analysis to evaluate the hypothesis that subchondral bone cysts in the osteoarthrotic hip joint may be the result of microfractures caused by localized cartilage defects or a thinned layer of cartilage. We evaluated the equivalent bone stress (von Mises (VM) stress) in the cancellous bone as an indicator of potential microfractures and further development of cystic lesions. RESULTS: Cartilage defects induced stress peaks in the subchondral bone. This peak stress distribution corresponded to the clinical observation of development of acetabular and femoral subchondral cysts in a "kissing" position. A femoral subchondral bone cyst induced a stress peak at the corresponding acetabular site, whereas subchondral acetabular cysts did not increase stress in the femoral head. Acetabular cysts showed an increased level of stress at the lateral and medial border of the lesion which was much higher than the stress levels in the femoral head, indicating a tendency to faster growth. INTERPRETATION: Our study supports the theory that stress-induced bone resorption may cause development of subchondral bone cysts in osteoarthrosis.     

An atypical aneurysmal bone cyst of the head of the humerus, arthroscopic treatment: a case report

Curettage and bone grafting are the accepted methods of treatment of aneurysmal bone cysts. Unfortunately, recurrence is common. We treated a patient with atypical aneurysmal bone cyst of the head of the humerus that lacked aneurysmal dilatation by arthroscopic curettage without bone grafting. New bone formation and remodeling was observed in this patient. There was no evidence of recurrence. Arthroscopic curettage without bone grafting is a simple and effective treatment for aneurysmal bone cyst.     

Treatment of a simple bone cyst of the calcaneus by endoscopic curettage with cancellous bone injection

The authors report a case of simple bone cyst involving the calcaneus, treated by curettage under endoscopy with cancellous bone injection, and its course and follow-up at two years. This new technique has not yet been published for simple bone cysts of the calcaneus. Endoscopic curettage of the cavity of a simple bone cyst can be advocated for the calcaneus to minimize incisions and to avoid cutaneous complications.     

Radiographic changes and clinical results of osteochondral defects of the talus with and without subchondral cysts

BACKGROUND: Subchondral cysts are a type of osteochondral defect of the talus and can be a source of chronic ankle pain. The treatment modality of this cystic lesion is similar to that of other osteochondral defects, but results from previous reports are controversial. Therefore, we compared the clinical results and radiographic changes in small subchondral talar cystic lesions (less than 1.5 cm2) to other noncystic defects after arthroscopic operations without bone grafting. METHODS: The review covered about 2 years (January, 2001 to April, 2003) and included 38 patients with an average age of 36.9 years. Followup ranged from 24 to 36 months. Arthroscopic microfracture or abrasion arthroplasty was performed on 20 defects with subchondral cysts and 18 defects without cysts. Clinical results were assessed by the ankle-hindfoot scale of the American Orthopaedic Foot and Ankle Society (AOFAS); radiographic changes were assessed by the transverse long diameter and the area (mm2) of the cyst on digital radiographs using a PACS (Picture Archiving Communication System). RESULTS: At the last followup, AOFAS clinical scores improved similarly in cystic and noncystic defects. The average diameter of the cysts decreased from 8 +/- 2 mm to 6 +/- 2 mm (p < 0.01). The area attributed to the cyst also decreased, from 49 +/- 17 mm2 (24 to 84 mm2) to 23 +/- 8 mm2 (4 to 34 mm2) (p < 0.01). There were no differences in the clinical results between the cystic and noncystic defects. CONCLUSIONS: Good clinical and radiographic results were obtained after arthroscopic treatment of osteochondral defects with a small subchondral cyst. Our results suggest that a small cystic lesion can be treated by arthroscopic microfracture or abrasion arthroplasty and that the existence of a small cyst in an osteochondral defect lesion may not affect the postoperative prognosis.     

Primary aneurysmal bone cyst of the patella: a case report

Aneurysmal bone cysts account for less than 1% of primary bone tumours and have a predilection for the metaphyses of the long bones of the leg. Only 1% of all aneurysmal bone cysts occur in the patella. We report on a 30-year-old man with a primary aneurysmal bone cyst in the right patella treated with curettage. The defect was filled with demineralised bone matrix and allogeneic cancellous bone graft. At the 1.5-year follow-up, the bone graft was well incorporated, the patient experienced no pain or tenderness and had a full range of knee movement.     

Arthroscopic Bone Grafting of Talar Bone Cyst Using Posterior Ankle Arthroscopy

A subchondral cyst of the talus frequently occurs with an osteochondral lesion of the talar dome. Debridement, curettage, and bone grafting through the articular defect was frequently the recommended treatment in reported studies for a massive cyst. We report a case of a massive cyst of the talar body with a small osteochondral lesion of the talar dome. Our patient was successfully treated by curettage and bone grafting of the cyst using posterior ankle arthroscopy, with minimal disruption of the articular surface of the talar dome.     

Endoscopic curettage and allografting of simple bone cysts of the calcaneus in young soccer players: Report of three cases

Open curettage with bone graft has been the traditionally suggested surgical treatment for the symptomatic simple (or unicameral as they used to be called) calcaneal bone cyst. Less invasive endoscopically assisted treatment with curettage and bone grafting with allograft have recently provided less postoperative morbidity. The aim of the present study is to present our experience with this method in young soccer athletes. Between April 2014 and May 2016 three consecutive young soccer players with symptomatic calcaneal bone cysts underwent endoscopic curettage, and percutaneous injection of demineralized bone matrix allograft. The mean age was 17.3 (16, 17 and 19 years old), and the mean follow-up was 32.1 (range 24–47) months. Both radiographic and functional follow-up, using the AOFAS score, showed good to excellent results. All lesions were radiographically healed. Preoperative AOFAS score (max. 100 pts) was 78.6 ± 4.7, improving to 98.0 ± 4.1. The patients returned to their initial level of sports activities within 18.3 (range 17–19) weeks after surgery. Evidence suggests an earlier return to sports using bone substitutes. However, the present study showed that endoscopic curettage and percutaneous injection of bone allograft is also an excellent treatment option for young athletes with a symptomatic calcaneal bone cyst.Level of clinical evidence4.     

Treatment of aneurysmal bone cyst]

The authors present the results of surgical treatment of 16 cases of aneurysmal bone cyst between 1998 and 2000. Age of patients at the onset of symptoms ranged from 5 to 15 years (average 11.3 years). In 12 cases the cysts were aggressive, and in 5 cases they were active (according to the capanne classification). In 12 cases the characteristic lining of the cyst was removed, curettage was performed and bone grafts were inserted into the bone cavity. In 3 cases autografts were used, in 2 cases both allografts and autografts were used, and in 7 cases only allografts were applied. Two cysts of the fibula were removed en-bloc, a cyst located in the scapule was treated with radiotherapy. In 15 cases the cyst was successfully managed surgically. While in 1 case a revision procedure was performed.