AN ADJUNCTIVE USE OF ASFOTASE ALFA AND ZOLEDRONIC ACID AFTER SPINAL SURGERY IN NEUROFIBROMATOSIS TYPE 1 RELATED DYSTROPHIC SCOLIOSIS

Abstract

Objective:

Dystrophic scoliosis is a serious skeletal manifestation of neurofibromatosis 1 (NF1). The condition requires surgical intervention that is frequently associated with poor outcome due to the high rate of impaired bone healing, pseudoarthrosis, and loosening of the spinal instrumentation. New therapeutic approaches are needed to improve surgical outcomes.

Methods:

Clinical, laboratory, and radiographic data are presented.

Results:

A 54-year-old woman with severe NF1 related dystrophic scoliosis and 3 prior surgical interventions underwent revision of lumbar fusion with intraoperative recombinant human bone morphogenetic protein (rhBMP-2) for loosening and a fracture of the left vertical rod at the L4 pedicle screw connection. Two days after surgery, a computed tomography (CT) scan revealed a left posterior iliac periscrew fracture. Given a high risk of mechanical failure, zoledronic acid and asfotase alfa were also administered at 3 and 7 months after surgery. At 14 months after surgery, back pain improved, and a CT scan showed stable spinal fusion and a healed left posterior iliac screw fracture.

Conclusion:

Combination therapy including asfotase alfa with rhBMP-2 and bisphosphonate resulted in solid arthrodesis after spinal surgery in NF1-related dystrophic scoliosis.

INTRODUCTION

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, caused by mutations in the neurofibromin gene (1). NF1 is characterized by the presence of café-aulait macules, neurofibromas, Lisch nodules, optic gliomas, skinfold freckling, vasculopathy, learning disabilities, and distinctive skeletal changes (bowing of the tibia, pseudoarthrosis, and vertebral dysplasia) (1,2).

Dystrophic scoliosis is a rare and serious skeletal manifestation of NF1 characterized by a sharp angulation involving segments of 4 to 6 vertebrae, vertebral rotation, vertebral scalloping, vertebral wedging, and rib penciling (3–5). The rapid progression of a dystrophic curve requires early spinal intervention, but the postsurgical course is often complicated by poor bone healing, dural ectasia, and pseudoarthrosis (60 to 100% of patients with NF1 receive posterior spinal fusion) (6). Patients may experience breakage or loosening of the spinal instrumentation leading to significant back pain and neurologic complications (3–5).

Bone pathology in NF1 is complex. Bone density is generally decreased compared with healthy individuals (7,8). Bone histomorphometry from individuals with NF1 and pseudoarthrosis shows excessive deposition of unmineralized osteoid, increased numbers of osteoblasts and osteoclasts, and reduced trabecular bone volume (7). Similar to humans, NF1-deficient mice also show skeletal dysplasia and poor mineralization, which is largely attributed to the accumulation of inorganic pyrophosphate (PPi), a potent inhibitor of bone mineralization, and reduced expression of alkaline phosphatase (ALP) (9). Furthermore, NF1 haploinsufficient mice have markedly increased osteoclastogenesis and are hyper-responsive to RANKL, which leads to increased osteoclast survival, proliferation, and resorption activity (10).

Addressing all aspects of metabolic bone defects in NF1 by increasing bone formation, reducing bone resorption, and improving mineralization would be expected to be beneficial for NF1-related bone abnormalities. Combination therapy using recombinant human bone morphogenetic protein BMPs (rhBMPs) together with bisphosphonates have been proposed for the treatment of pseudoarthrosis of the tibia in patients with NF1 (11). However, poor bone mineralization has not been addressed.

Asfotase alfa, a recombinant human tissue nonspecific isoenzyme of ALP has been approved for the treatment of pediatric-onset hypophosphatasia (HPP) (12). Administration of asfotase alfa in HPP reduces serum PPi concentration and increases bone mineralization (12). In a mouse model of NF1, asfotase alfa improved bone mineralization and bone mineral density (9). Its use in patients with NF1 has not been previously reported. Here we describe a patient with severe NF1 related dystrophic scoliosis and a history of failed surgical interventions after combination therapy that included surgical intervention, rhBMP-2, zoledronic acid, and asfotase alfa.

METHODS

Pyridoxal 5′-phosphate (PLP; vitamin B6) and serum PPi were measured using liquid chromatography–mass spectrometry (LC-MS) method at Biotrial (Newark, NJ). Levamisole and ethylenediaminetetraacetic acid (EDTA) containing tubes were used to inhibit high ALP activity resulting from asfotase alfa. Calcium, phosphorus, and creatinine were measured by biochromatic end-point, while 25-hydroxy-vitamin D was measured by LC-MS method. Parathyroid hormone, ALP, bone specific ALP (BSALP), osteocalcin, N-telopeptide (NTx), C-telopeptide (CTx), and procollagen type 1 intact N-terminal Pro (P1NP) were measured by immunoassay. CT of the thoracolumbar spine was obtained prior to surgery and 14 months after surgery. Renal ultrasound and comprehensive eye examination were performed before and after asfotase alfa treatment to evaluate for potential ectopic calcifications. The use of asfotase alfa was approved by the University of Minnesota’s Institutional Review Board (IRB#1609M94281) and was carried out under the United States Food and Drug Administration Investigational New Drug (IND#132845) single use expanded access. The patient was provided and signed an informed consent for the use of asfotase alfa.

CASE REPORT

A 54-year-old woman with a history of NF1-related dystrophic scoliosis, advanced dural ectasia (Fig. 1) and osteoporosis, underwent 3 prior spinal surgeries over a period of 7 years for advanced dystrophic scoliosis complicated by pseudoarthrosis. The patient has been followed annually at the spine clinic until 2 years after the third surgery when she developed acute, worsening back pain, and paresthesia of anterior thighs. A CT scan revealed peripheral lucency of the left posterior iliac screw indicative of loosening. Back pain persisted with a visual analog scale (VAS) pain score of 9 and an Oswestry low back disability score of 52% despite morphine treatment. The spinal instrumentation has progressively loosened over 3 years. A CT scan revealed advanced peripheral lucency of the left posterior iliac screw and a fracture of the left vertical rod at the L4 pedicle screw connection. Therefore, the patient underwent a revision of lumbar fusion including reinsertion of spinal instrumentation of T11 to sacrum, reinsertion of pelvic fixation, and posterior spinal fusion from T11 to the pelvis, along with intraoperative rhBMP-2 to enhance bone formation. A CT scan performed 2 days after surgery due to a sudden onset of stocking-like paresthesia of bilateral ankles without weakness, revealed lucency around the left posterior iliac screw with a new bony defect in the outer cortex at the tip of the screw suggestive of periscrew fracture (Fig. 2). Paresthesia of bilateral ankles gradually improved without intervention, and the patient ambulated safely before discharge. Given the patient’s severe dystrophic scoliosis and previous history of mechanical failure, the patient received 5 mg of intravenous zoledronic acid at 3 months after surgery to inhibit bone resorption and asfotase alfa (2 mg/kg 3 times/week subcutaneous injection for 6 months) starting at 7 months after surgery to improve bone mineralization.

Fig. 1.

A, Original radiograph of a patient aged 47 years showing severe dystrophic lumbar scoliosis. The arrow points to the marked left convex dystrophic scoliosis of the thoracolumbar spine, with apex at L3. This is a dystrophic curve because of the short, sharp angles, dural ectasia, vertebral body scalloping, vertebral wedging, and narrowed pedicles. B, Original CT lumbar spine of a patient aged 47 years showing severe dural ectasia throughout the lumbar, but most pronounced at L2 and L3, where prominent posterior vertebral body scalloping is seen. CT = computed tomography.

Fig. 2.

Postoperative CT scan performed 2 days after the recent spinal surgery showed: A, Stable lucency around the left posterior iliac screw (arrow); B, Fracture of the outer cortex of the bone at the tip of the left posterior iliac screw is seen (arrow). CT = computed tomography.

Baseline laboratory data revealed normal ALP, BSALP, PPi, PLP, and bone turnover markers (Table 1). CTx, NTx, and P1NP increased for at least 3 months after surgery. NTx and P1NP normalized within 5 months, while CTx was normal 11 months after zoledronic acid administration. During asfotase alfa treatment, ALP and BSALP activity were increased, indicative of the patient’s compliance with treatment. PPi and PLP remained within normal limits. The patient did not experience any adverse events following asfotase alfa treatment. Renal ultrasound and eye examination before and after asfotase alfa treatment revealed no ectopic calcifications. At the follow-up visit at 14 months after surgery, the patient reported decreased back pain with VAS pain score of 7 and Oswestry low back disability score of 42% and was able to stop morphine treatment. A CT lumbar spine showed stable instrumented spinal fusion and healed fracture at the tip of the left posterior iliac screw without loosening (Fig. 3). Unfortunately, the patient was lost to follow-up.

Table 1.

Laboratory Investigations During the Study Period

	Baseline (within 3 months before surgery)	~5 Days after surgery	3 Months after surgery	7 Months after surgery	8 Months after surgery, 1 month after starting AA	14 Months after surgery, 6 months after starting AA
Zoledronic acid			Xa
Asfotase alfa (AA)				AAb	AAb
Alkaline phosphatase (40–150 U/L)	58	86			>2,330	>2,330
Serum inorganic pyrophosphate (PPi) (1.00–5.82 μM)	1.11				2.3
Serum pyridoxal 5’-phosphate (PLP; vitamin B6) (2.81–26.7 ng/mL)	4.32				4.7
Parathyroid hormone (12–72 pg/mL)	37		73		65	66
Creatinine (0.52–1.04 mg/dL)	0.63	0.38	0.58		0.63	0.68
25-Hydroxyvitamin D (20–75 μg/L)	67		94		43	42
Total calcium (8.5–10.1 mg/dL)	8.5	8.4	9.0		8.8	8.7
Bone turnover markers
Bone specific alkaline phosphatase (postmenopausal woman: 7–22.4 μg/L)	12.3		19.1		1,949.5	1,751.1
Osteocalcin (11–50 ng/mL)	26	20	31		10	17
Procollagen type 1 intact N terminal Pro (P1NP) (postmenopausal woman: 16–96 μg/L)	83	87	120		43	54
C-Telopeptide (CTx) (postmenopausal woman: 104–1,008 pg/mL)	721	844	1,256			559
N-Telopeptide (NTx) (postmenopausal woman: 6.2–19 nM BCE)	15.6	17.9	25.5		10.6	14.4

^aX indicates zoledronic acid infusion administration.

^bIndicates 6 months of asfotase alfa (AA) treatment during this period.

Fig. 3.

A CT scan performed 14 months after surgery and following 6 months of asfotase alfa treatment showed marginal lucency around screw without evidence of loosening (upper arrow) and healed fracture at the tip of the left posterior iliac screw (lower arrow). CT = computed tomography.

DISCUSSION

To our knowledge, this is the first case of the use of asfotase alfa and bisphosphonate in combination with surgical intervention and rhBMP-2 that resulted in solid arthrodesis and enhanced bone healing in a patient with NF1-related dystrophic scoliosis and 3 prior spinal surgeries. Because of the nature and complexity of the disease, management of dystrophic scoliosis is challenging, and clinical outcome can be unsatisfactory due to pseudoarthrosis, poor bone healing, pain, and neurologic symptoms. Thus, combination therapy with drugs that work through different mechanisms to optimize bone homeostasis might be an alternative treatment strategy for treating NF1-related dystrophic scoliosis.

Both rhBMPs and bisphosphonates have been previously used as an adjunct to surgical intervention (11). The use of rhBMPs has been well established in spinal fusion surgery, but the outcomes of its use alone in NF1-related pseudarthrosis were inconsistent (13,14). A retrospective case series has shown that a combined use of rhBMPs and bisphosphonates may provide better outcomes than rhBMPs therapy alone in children with NF1 and pseudoarthrosis of the tibia (11). Nevertheless, another key component of the pathogenic pathway in patients with NF1, which is impaired mineralization, has not been previously addressed in humans.

The mechanism by which a recombinant form of ALP (asfotase alfa) may have contributed to a surgical repair in this case has not been investigated. De la Croix Ndong et al (9) previously demonstrated that NF1 deficiency in a mouse model is associated with elevated levels of extracellular PPi due to increased expression of genes promoting PPi synthesis (9). In addition, NF1 ablation prevents BMP2-induced osteoprogenitor differentiation and expression of ALP. In NF1-deficient mice, asfotase alfa showed positive effects on the skeletal phenotype by hydrolyzing PPi and promoting mineralization (9). The use of asfotase alfa in patients with NF1-related dystrophic scoliosis has not been established. However, its use has been shown to decrease PPi levels in patients with HPP into the normal range and improve bone mineralization (12,15). We postulated that a combination therapy aimed at increasing bone formation, reducing bone resorption, and improving bone mineralization (in a mechanistically similar manner to HPP) would be effective in promoting solid arthrodesis and bone healing after spinal surgery. Therefore, we added asfotase alfa and bisphosphonate to the existing regimen (surgery with rhBMPs). Although it is not possible to delineate each treatment’s effect on bone, our result suggests that a combination therapy prevented mechanical failure and improved back pain in a patient with NF1-related dystrophic scoliosis.

Since this is a single case, it is not possible to prove whether this approach is superior to previously reported strategies or which component played the major role in enhancing solid arthrodesis. We elected to administer zoledronic acid to inhibit bone resorption first followed by asfotase alfa to target bone mineralization after surgery (at recommended doses currently approved for HPP), but the most optimal timing of treatment remains to be determined. Unfortunately, the post-surgical follow-up period was relatively short since the patient was lost to follow-up, thus, it was impossible to determine the long-term effect of a combination therapy on bone healing and pain control. Moreover, we did not have PPi and PLP values at the end of asfotase alfa treatment.

CONCLUSION

Combination therapy with rhBMP, bisphosphonate, and asfotase alfa achieved solid arthrodesis after spinal surgery in a patient with NF1-related dystrophic scoliosis. This case suggests that addressing bone formation, resorption, and mineralization may provide hope for a better outcome in the most challenging cases.

Abbreviations

ALP

alkaline phosphatase

BSALP

bone specific ALP

CTx

C-telopeptide

HPP

hypophosphatasia

NF1

neurofibromatosis 1

NTx

N-telopeptide

P1NP

procollagen type 1 intact N terminal pro

PLP

pyridoxal 5′-phosphate

PPi

inorganic pyrophosphate

rhBMPs

recombinant human bone morphogenetic protein