Hypophosphatasia (HPP) is a rare metabolic bone disease caused by deficient alkaline phosphatase activity, leading to impaired mineralization. While total knee arthroplasty (TKA) is a common treatment for end-stage knee arthritis, its outcomes in patients with metabolic bone disorders like HPP are poorly documented.

We describe a 49-year-old woman with genetically confirmed adult-onset HPP who underwent primary and revision TKA due to persistent joint pain and mechanical symptoms. Both procedures failed due to aseptic loosening despite appropriate surgical technique and implant positioning. Intraoperative findings revealed highly porous, fragile bone with poor vascularization.

Although a direct causal relationship cannot be established, HPP-related bone fragility may impair osseointegration and predispose to early implant failure. This case highlights the need to consider underlying metabolic bone disorders in TKA candidates.

To our knowledge, this is the first reported case of recurrent aseptic TKA loosening in a patient with HPP. Further research is needed to clarify the role of HPP in prosthetic failure.

aseptic loosening, hypophosphatasia, metabolic bone disorder, total knee revision

Total knee arthroplasty (TKA) is a common surgical intervention for end-stage knee arthritis, aiming to alleviate pain and improve function. However, despite advances in surgical techniques and implant design, TKA failure remains a significant concern, with aseptic loosening emerging as a leading cause of implant revision. Aseptic loosen­ing is characterized by a gradual loss of fixation between the prosthetic components and the surrounding bone, which causes pain, instability, and, eventually, implant failure. Studies have shown that 15%–30% of patients report persistent pain following TKA.^[1]

Wear debris-induced inflammation is recognized as a primary mechanism, wherein the generation of particulate debris from prosthe tic materials triggers an immune response and macrophagic and cytokine activation that causes a hyperactivity of osteoclasts in the bone-implant interface, resulting in osteolysis and subsequent bone resorption. The size, volume, and biocompatibility of wear particles play crucial roles in modulating the severity of this inflammatory response.

Different patient-related or implant-related situations can be associated with aseptic loosening in TKA. In addition, implant-related factors such as design features, surface characteristics, and fixation methods have a significant impact on the risk of aseptic loosening. Poor component alignment, malpositioning, and instability can also create stress concentrations that accelerate wear and compromise the bone-implant interface.

In addition, patient-related factors such as age, weight, activity level, and underlying bone disease may contribute to implant failure by compromising bone quality and integrity.^[2] Osteoporosis, glucocorticoid use, and AR are more commonly described as patient-related factors associated with knee prosthesis failure.

Rare bone diseases are a group of rare clinical entities that can affect any structural component of bone, both cellular and inorganic, and the exact diagnosis is often difficult and late. Some of these pathologies affect the articular surface and lead to arthritis, which is often misdiagnosed as primary arthritis.

To our knowledge, there is no literature on a possible link between rare bone diseases and TKA failure.

Hypophosphatasia (HPP) is a rare disease characterized by deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity due to a genetic disorder with consequent impaired bone mineralization, bone remodeling, strength, and appropriate response to mechanical stress.^[3]

Clinical manifestations are very heterogeneous; the least severe form is characterized by non-specific symptoms in later age, such as osteoporosis, musculoskeletal pain, and chondrocalcinosis.

Authors describe a clinical case of a patient affected with hypophosphatasia and recurrent aseptic TKA loosening. They focused on the potential role of this genetic disease in implant failure.

A.F., a Caucasian 49-year-old woman, had been diagnosed with congenital hypophosphatasia (ALPL gene mutation) in 2016. Over the preceding years, she had suffered from multiple arthritis linked to chondrocalcinosis and chondropathy, for which she had taken colchicine and undergone surgery for a patellofemoral endoprosthesis of the right knee in 2016 (Fig. 1) .

Figure 1.

Anteroposterior and lateral views.

Additionally, in 2016, she was diagnosed with “cuneization” of some vertebral bodies, despite having a normal DEXA delta-T score.

In 2017, she received anabolic treatment with teriparatide, followed by therapy with fentanyl patches and asfotase alfa. However, after 3 months, she discontinued the therapy herself due to elevated liver enzymes and palpitations.

She came to our attention in 2020 due to pain in her right knee and underwent surgery for total knee arthroplasty. During the surgery, the patient was diagnosed with bilateral femoral condyle necrosis (Fig. 2) .

Figure 2.

Anteroposterior and lateral views after surgery.

Despite the surgery, she continued to experience pain in her right knee, which did not respond to pain medications. She also experienced myarthralgia and walking limitations, leading her to seek rheumatological evaluation in 2022. A scintigraphy revealed radiopharmaceutical accumulation in the right prosthetic knee and diffuse accumulation in multiple joints.

Due to persistent right knee pain and evidence of bone pathology on scintigraphy, a surgical revision of the prosthetic knee was performed in January 2023. During the revision, we observed mobilization of the tibial component on the medial side, and underneath it, the bone had high porosity, increased fragility, and low blood supply. The low-quality bone was removed, and the tibial side was prepared for implantation of the cemented revision component. Alignment of the components appeared satisfactory, and patellar tracking was deemed adequate (Fig. 3) .

Figure 3.

Anteroposterior and lateral views after revision surgery.

However, only one month after the revision, the patient presented again with right knee pain, knee sweeping, and walking limitations. Radiographic imaging did not reveal any mechanical issues, nor were there any laboratory or clinical signs of infection. A rheumatological evaluation was conducted, and the specialist prescribed a stronger analgesic therapy for the case, which included a corticosteroid for 15 days, colchicine, cyclobenzaprine (a muscle relaxer) for 7 days, tapentadol, and clodronate i.m. for 15 days.

The patient expressed frustration about the lack of long-term relief and ultimately declined further interventions.

Knee arthritis is a common disease, especially in the elderly. However, it can also affect younger people, and when it occurs, it is important to assess the causes of early-onset pathology. Some metabolic diseases leading to bone fragility or secondary arthritis can negatively affect the survival of the implant, even when the surgical technique is properly executed.

We could not find studies in literature linking TKA failure directly to metabolic bone diseases. However, it is well established that osteoporosis is an independent risk factor for aseptic loosening in total joint arthroplasty (TJA). Therefore, it is reasonable to suggest that metabolic diseases leading to poor bone quality may be associated with TJA failure.^[4]

The case study outlines a total knee arthroplasty (TKA) in a patient with double aseptic bone loosening, a condition caused by hypophosphatasia. Prior to undergoing the surgical procedure, the patient had received asfotase therapy for a duration of three years. However, this treatment was discontinued due to the emergence of adverse effects. Additionally, the patient had received a brief course of anabolic treatment involving teriparatide.

She underwent knee arthroplasty for knee osteoarthritis, despite her young age, due to HPP joint complications.

Although the surgical technique was performed correctly, two aseptic loosening events near the operation were described.

Aseptic bone loosening is a challenge for orthopedic surgeons. Mavrogenis AF et al. consider an implant osseointegrated when no movement between bone and implant is present. They also assert that the osseointegration process reflects the lack of a physiological negative tissue response due to a foreign body reaction.^[5]

Macrophagic activity aims to degrade particles originating from the implant and therefore recognized as foreign bodies.

Implant particles present different sizes; the smallest ones can be included in macrophagic lysosomes and are able to start a self-sustaining process producing necrosis.^[6]

Several pharmacological approaches are hypothesized to be able to reduce macrophagic activities preventing bone loosening, such as antiosteoporosis drugs.^[7]

Nowadays, TKA guarantees a good clinical outcome in late stages of arthritis. However, in some cases, surgical revision of the implant is required (from worldwide registers, the mean revision rate for TKA is 5.63%).^[8]

From the analysis of 36,307 cases of revision total knee arthroplasty (RTKA) from worldwide arthroplasty registers, Sadoghi et al. found that the most common causes of TKA revision were aseptic loosening (29.8%) followed by septic loosening (14.8%), pain without other reasons (9.5%), wear (8.2%), instability (6.2%), implant breakage (4.7%), and periprosthetic fractures (3%).^[9]

Osteolysis represents the main radiographic sign of TKA loosening: the particulate debris produced by the bearing process of the prosthesis component is the main factor that induces osteolysis. Debris, particularly smaller debris, is more easily activated by macrophages, which release pro-inflammatory factors, activating osteoclasts and causing bone loss.^[10-12]

Prieto-Alhambra et al. published data from the United Kingdom General Practice Research Database covering the years 1986–2006. Of the 41,995 patients undergoing primary hip or knee arthroplasty, they identified 1912 bisphosphonate (BP) users. They concluded that using BP in patients undergoing lower limb arthroplasty resulted in a nearly 2-fold increase in implant survival time.^[13]

Harris et al. noted that osteoporosis was associated with a 2-fold increased risk of 5-year revision for periprosthetic fractures after TKA.^[14]

It is plausible that also metabolic bone disorders, such as osteomalacia, hypophosphatasia, hypovitaminosis D, hypocalcemia, and primary and secondary hyperparathyroidism, can adversely affect bone quality and consequentially may contribute to complications in orthopedic procedures like total knee arthroplasty. While direct studies linking these conditions to TKA loosening are limited, understanding their impact on bone health provides insight into potential risks associated with implant outcome.

Vitamin D deficiency can lead to decreased calcium absorption, resulting in hypocalcemia. Chronic hypocalcemia disrupts bone remodeling and mineralization, potentially leading to osteomalacia, a condition characterized by defective bone mineralization. This condition leads to the accumulation of unmineralized bone matrix, resulting in bone pain, muscle weakness, and increased fracture risk. The compromised bone integrity associated with osteomalacia could potentially affect the stability of orthopedic implants.^[15]

Secondary hyperparathyroidism commonly occurs in response to chronic kidney disease, vitamin D deficiency, inadequate calcium intake or absorption, and other clinical conditions.^[16]

Elevated parathyroid hormone (PTH) levels increase bone resorption, resulting in decreased bone density and structural integrity. This enhanced bone turnover and loss of bone mass could potentially compromise the fixation and longevity of orthopedic implants.

Primary hyperparathyroidism is an endocrine disorder associated with high serum levels of calcium and parathyroid hormone. Excessive secretion of PTH can lead to bone loss, which in turn may result in mobilization and implant failure after TKA. The excessive and inappropriate secretion of PTH can stimulate osteoclasts at the cortico-medullary junction and weaken the cortical bone. However, there is currently no evidence in literature reporting an association between prosthesis loosening and primary hyperparathyroidism.^[17,18]

The patient described in our case report was affected by HPP in the adult form.

Hypophosphatasia is a rare metabolic disorder caused by mutations affecting alkaline phosphatase activity, leading to defective bone mineralization. This results in weakened bones and an increased risk of fractures. The biochemical marker of the disease is low defective alkaline phosphatase activity, which results in defective mineralization of bones and/or teeth. Its severity is highly variable (ranging from fetal death to only dental pathology in adults). The disease can be inherited in either an autosomal recessive or dominant manner (associated with milder phenotypes).

The manifestations of this disease are extremely variable. Depending on the age of symptom onset, it can be classified into 6 different forms. Each form may have specific clinical characteristics, and not all possible clinical manifestations may be present simultaneously.

The diagnosis of HPP is often delayed in children and, particularly, in adults. The most frequent symptoms are osteomalacia, pathological fractures such as metatarsal and subtrochanteric fractures (like atypical femoral fractures associated with antiresorptive therapy), arthritis and chondrocalcinosis, joint pain, muscle stiffness, and dental problems.

In cases of delayed diagnosis, individuals may suffer from significant multisystemic complications related to the disease. Asfotase alfa is approved to treat HPP, and its use is crucial in changing the prognosis of the disease. Teriparatide and romosozumab have also been used off-label and demonstrated positive results in accelerating fracture healing and treating osteoporosis.^[19]

In conclusion, to our knowledge this is the first case report describing prosthetic loosening associated with HPP.

In our case, the prosthesis failed twice despite the correct implantation technique. The patient had never been pain-free, and the implant eventually underwent aseptic loosening.

Given the presence of a rare metabolic bone disease, we tend to associate double prosthesis failure with HPP in this case, although there is no direct evidence of a cause-and-effect mechanism.

Ethical statement

• The authors declared that no clinical trials were used in the present study.
• The authors declared that no experiments on humans or human tissues were performed for the present study.
• Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
• The authors declared that no experiments on animals were performed for the present study.
• The authors declared that no commercially available immortalized human and animal cell lines were used in the present study.

Conflict of interest

The authors have declared that no competing interests exist.

Artificial Intelligence (AI) use

The authors accept full responsibility for the content of the manuscript, including the disclosure of any use of AI. No AI tools were used in the preparation of this manuscript.

Funding

No funding was reported.

Author contributions

All authors have contributed equally.

Author ORCIDs

Giulia Lazzeri https://orcid.org/0009-0008-6208-1447

Damiano Antognetti https://orcid.org/0000-0002-0438-2494

Data availability

All of the data that support the findings of this study are available in the main text.