The effect of therapies for osteoporosis on spine fusion: a systematic review

The Spine Journal 13 (2013) 190–199

Review Article

The effect of therapies for osteoporosis on spine fusion: a systematic review Brandon P. Hirsch, MDa,*, Aasis Unnanuntana, MD, MSb, Matthew E. Cunningham, MD, PhDc, Joseph M. Lane, MDc a

Department of Orthopaedic Surgery, University of Miami/Jackson Health System, PO Box 016960 (D-27), Miami, FL 33101, USA b Department of Orthopaedic Surgery, Siriraj Hospital, Mahidol University, 2 Prannok St, Bangkok, Thailand 10700 c Department of Orthopaedic Surgery, Hospital for Special Surgery, 535 East 70th St, New York, NY 10021, USA Received 24 July 2011; revised 6 December 2011; accepted 28 March 2012

Abstract

BACKGROUND CONTEXT: Fusion of the spine requires de novo bone formation and remodeling, processes that rely heavily on the action of the osteoblast and osteoclast. Bisphosphonate drugs and intermittent parathyroid hormone (PTH) therapy are widely prescribed to treat osteoporosis and act on the osteoblast/osteoclast complex. The impact of these medications on spine fusion is not known. PURPOSE: To evaluate the available evidence on the potential impact of bisphosphonates and PTH on fusion rate and fusion quality in spinal arthrodesis. STUDY DESIGN: A systematic review of the literature. PATIENT SAMPLE: All available literature regarding the impact of bisphosphonates and PTH on spinal fusion. OUTCOME MEASURES: Fusion rate and histologic, microstructural, or biomechanical measures of fusion quality. METHODS: A systematic review of the literature published between 1980 and 2011 was conducted using major electronic databases. The results of studies meeting criteria for inclusion were then aggregated and examined for consensus on the effect of these medications on spine fusion. RESULTS: The literature contained 18 animal studies and one clinical trial investigating the impact of these medications on spine fusion. Most animal studies evaluating the impact of bisphosphonates on fusion rate have not found statistically significant changes with treatment, although this fact may be attributable to low statistical power. The animal literature does suggest that bisphosphonate therapy results in a less histologically mature fusion mass; however, the impact of these changes on fusion mass biomechanics is unclear. The only available human study suggests that these bisphosphonates may increase the radiographically defined fusion rate but did not demonstrate an impact on clinical outcome. In animals, PTH improves the fusion rate and fusion mass microstructure, but data on its effect on fusion mass biomechanics are lacking. No studies have evaluated the impact of PTH on spine fusion in humans. CONCLUSIONS: In animals, bisphosphonate therapy appears to impede maturation of the fusion mass, with an unclear effect on mechanical strength. This effect was not seen in the lone human study, which suggested that these medications improved the radiographically defined fusion rate. The available animal studies on intermittent PTH treatment suggest that it may improve fusion rate

FDA device/drug status: Approved for treatment of osteoporosis (Bisphosphonate drugs and intermittent parathyroid hormone therapy). Author disclosures: BPH: Nothing to disclose. AU: Nothing to disclose. MEC: Nothing to disclose. JML: Stock Ownership: CollPlant, Inc (20,000 shares); Consulting: Amgen (B, Paid directly to institution/employer), BioMimetics, (C, Paid directly to institution/employer) CollPlant (C, Paid directly to institution/employer), DFine (B, Paid directly to institution/employer), Graftys (B, Paid directly to institution/employer), Zimmer (C, Paid directly to institution/employer); Speaking/Teaching Arrangements: Eli Lilly (D), Novartis (B), Warner Chilcott (B); Trips/Travel: 1529-9430/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spinee.2012.03.035

Zimmer (A, Paid directly to institution/employer); Scientific Advisory Board: Zimmer (A); Research Support (Staff/Materials): Cohn Foundation (F, Paid directly to institution/employer). The disclosure key can be found on the Table of Contents and at www. TheSpineJournalOnline.com. * Corresponding author. Department of Orthopaedic Surgery, University of Miami/Jackson Health System, PO Box 016960 (D-27), Miami, FL 33101, USA. Tel.: (305) 585-1315. E-mail address: [email protected] (B.P. Hirsch)

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and fusion mass microstructure. Given the widespread use of these agents, further investigation into their impact on human spine fusion is necessary to inform the care of patients with osteoporosis who are undergoing spine surgery. Ó 2013 Elsevier Inc. All rights reserved. Keywords:

Spine fusion; Osteoporosis; Bisphosphonates; Parathyroid hormone; Pseudarthrosis

Introduction Spine fusion is among the most common orthopedic procedures, with more than 250,000 cases performed each year in the United States [1,2]. Successful spine fusion necessitates formation and remodeling of new bone, processes that rely heavily on the involvement of the osteoblast/osteoclast complex. Pseudarthrosis is the most frequently encountered complication of the procedure, occurring in 10% to 30% of the cases [2]. This presents a difficult problem for patients and clinicians, as it often leads to pain and the need for reoperation. New approaches to preventing pseudarthrosis are of great interest in musculoskeletal research. Osteoporosis is the most common metabolic bone disease in the United States, with an estimated 10 million patients affected [3]. Therapies for osteoporosis universally act on the coupled system of osteoblast and osteoclast activity. Bisphosphonates, the largest class of antiresorptive medications, are widely prescribed to treat osteoporosis. Their mechanisms of action are threefold. Bisphosphonates inhibit osteoclastogenesis in the bone marrow, decrease osteoclast activity at the bone surface, and shorten osteoclast life span by increasing apoptotic cell death [4]. The newest class of antiosteoporosis drugs are the anabolic agents, of which only parathyroid hormone (PTH) is currently available for use in the United States. The anabolic effect of intermittent PTH administration occurs via the activation of osteoblast cell surface receptors, which are coupled to downstream messengers capable of inducing the production of several growth factors, including insulin-like growth factor 1. The resultant increase in osteoblast activity increases bone mass, primarily by increasing the quantity of cancellous bone [5]. The targets of action of these medications have motivated many to ask what effect they may have on the biology of spine fusion. The sequence of bone graft incorporation in spine fusion has many similarities to that of fracture healing, a process that has been well studied in musculoskeletal biology [6,7]. The effects of bisphosphonates and PTH on fracture healing have been the focus of several such experiments [7]. In general, data from animal models have shown that bisphosphonates induce the formation of larger fracture calluses containing less mature bone [8–10]. The impact of these changes on the mechanical strength of the healed fracture is unclear, with many studies yielding conflicting results [11–14]. Animal studies on the effect of PTH suggest that its anabolic action enhances fracture healing, increasing the strength of the healed bone and speeding the process of bone formation and remodeling [15–19].

With millions of patients receiving treatment for osteoporosis and more than one-quarter of a million patients undergoing spinal fusion in this country each year, overlap between these two patient populations is to be expected. Given the mechanisms of action of these drugs and their relationship to the biology of bone formation and remodeling, the question arises as to what role antiosteoporotic therapies might play in influencing the probability of a successful fusion. This systematic review is designed to investigate the potential impact of bisphosphonates and PTH therapy on fusion rate and fusion mass quality in spinal arthrodesis.

Methods A comprehensive search of the literature was performed to identify articles published between 1980 and January 2011 that evaluated the effects of either bisphosphonates or PTH on spine fusion. Specifically, we were interested in studies that examined the impact of these medications on fusion rate or fusion quality. An electronic search of PubMed (MEDLINE), EMBASE via Scopus, and BIOSIS was conducted using the search terms ((spinal fusion) or pseudarthrosis) AND (bisphosphonates OR etidronate OR clodronate OR ibandronate OR alendronate OR risedronate OR pamidronate OR zoledronate OR parathyroid hormone OR teriparatide). A reviewer then screened the titles and abstracts of articles returned by the search for inclusion. The reference lists of included studies were also screened for relevant entries. During screening, articles meeting any of the following criteria were excluded from the review: (1) studies that were not conducted in an in vivo system, either animal or human, (2) studies that did not evaluate spinal fusion, (3) studies that did not use control subjects, (4) studies that did not treat evaluate subjects receiving bisphosphonates or PTH, (5) studies that did not include at least one of the following: a measurement of fusion rate or a biomechanical, histologic, or microstructural assessment of fusion quality, (6) studies that did not perform statistical analysis, or (7) case reports. The search strategy yielded 55 articles from the literature. Screening of the titles and abstracts of these articles and their associated references identified 19 articles for inclusion (Figure). Relevant information from each included study was extracted and collected into an electronic spreadsheet. Demographic data on the model studied, study design, medication type, the number of subjects, and the dosage, duration, and timing of treatment were collected. The fusion rate and

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Figure. A Quality Of Reporting Of Meta-analyses (QUORUM) diagram outlining the results returned by the search strategy and the number of studies excluded by criteria.

methodology used to calculate fusion rate were recorded for each article. Data regarding the assessment of fusion quality and the associated methodology were also recorded. This included, but was not limited to, biomechanical testing, histologic evaluation, and microstructural analysis via computed tomography (CT). Information concerning the effects on the bone/implant interface in instrumented spine fusion was also collected when available. On several occasions, studies used multiple treatment groups, each receiving a different medication of interest. When this occurred, each comparison between a treatment group and the control group was considered a distinct experiment and given its own entry within the spreadsheet. Information about the statistical significance of findings was also collected. Once all data were compiled, an assessment of each medication’s effect on spinal fusion rate and measures of spinal fusion quality was made. The heterogeneity of the methodology used in the included studies precluded meta-analysis.

Results Nineteen articles returned by the search strategy met the criteria for inclusion. All articles were of a randomized, controlled, and blinded experimental design. Eighteen studies were conducted in animal models. Of these, 14 of the articles studied bisphosphonates and four studied PTH. The literature contained one study on the effect of bisphosphonates on spine fusion in humans. No studies evaluated the effect of PTH on spinal fusion in humans. The effect of bisphosphonates on spinal fusion in animal models The specific bisphosphonates studied in conjunction with animal models of spine fusion included alendronate

(10 studies), risedronate (one study), zoledronate (one study), and pamidronate (two studies). Information on the animal model, drug, drug dosage, dosing schedule, and number of subjects used in each study appears in Table 1. Eleven articles involving bisphosphonates used a posterolateral fusion (PLF) model. Two articles examined the effect of bisphosphonates on anterior interbody fusion. All studies controlled for the amount of bone graft used. Of the 14 animal studies involving bisphosphonate drugs, 12 evaluated the rate of successful fusion. All 12 of the animal studies assessing the rate of spinal fusion used the technique of manual palpation, radiographs, or a combination of the two to determine whether levels were fused or not. The findings of these experiments and a description of their methodology for defining fusion are shown in Table 2. Of the 12 studies using manual palpation and/or radiographs, only one was able to detect a difference in fusion rates between control animals and animals treated with bisphosphonates. In this study of a noninstrumented rodent posterolateral lumbar fusion model, manual palpation alone detected a fusion rate of 95% in controls versus 50% (p5.002) in animals treated with 5 mg/kg/d and 40% (p!.0001) in animals treated with 50 mg/kg/d of subcutaneous alendronate for a duration of 8 weeks [20]. Five studies used a histologic assessment of fusion rate in addition to a manual and radiographic assessment [21–25]. The results of their analyses and methods used to define fusion are listed in Table 3. Of the five studies that used a histologic definition of fusion, two found a significant difference between control and treated animals using a threshold Emery score [26] to define fusion. In a rabbit model of noninstrumented lumbar PLF, control animals had a fusion rate of 76% versus 45% (p5.004) for animals treated with oral alendronate for 8 weeks [21]. In another study of a rodent model of noninstrumented posterolateral lumbar fusion, controls had a fusion rate of 73% versus 34% (p5.004) for subjects treated with 10 weeks of oral risedronate [22]. The three remaining studies that made a histologic determination of fusion rate used different criteria and did not show a significant difference in fusion rate between groups [23–25]. Thirteen of the 14 animal studies dealing with bisphosphonates made a histologic, microstructural or biomechanical assessment of fusion. Of these 13 studies, 10 focused on the quality of the fusion mass itself, whereas the other two were concerned with the properties of bone/implant interface in instrumented fusion. Seven studies focused on the histologic characteristics of the fusion mass [20,23–25,27,28]. The findings of these studies are shown in Table 4. Five articles found a significant difference in the histologic composition of fusion masses, whereas two found no difference. Four of these studies, with varying dosages and duration of alendronate treatment, described a significantly higher proportion of immature or unremodeled bone within the fusion mass of treated subjects [20,23,27,28]. Authors from three of these

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Table 1 Demographic information on studies evaluating the effect of bisphosphonates on spine fusion Study

Animal

Model

Drug

Dose

Duration

Takahata et al. [27]

Rat (ovx)

PLF w/ autograft

Alendronate

0.01 mg/kg/d (SQ)

4 or 8 wk

Nakao et al. [29]

Rat (ovx)

PLF w/ autograft

Alendronate

70 mg/kg/wk (SQ)

8 wk

Gezici et al. [22]

Rat

PLF w/ autograft þ DBM

Risedronate

10 mg/kg/wk (oral)

10 wk

Sama et al. [28]

Rat

PLF L4/L5 (pseudarthrosis model)

Alendronate

2, 4, or 6 wk

Huang et al. [20]

Rat

PLF w/ autograft

Alendronate

Babat et al. [30]

Rabbit

PLF w/ autograft

Pamidronate

Bransford et al. [31]

Rabbit

PLF w/ autograft

Zoledronate

Therapeutic: 1 mg/kg/wk Overdose: 10 mg/kg/wk (SQ) Therapeutic: 5 mg/kg/wk Overdose: 50 mg/kg/wk (SQ) Preop: 1.2 mg 3/wk Postop: 0.6 mg/d Local: 20 mg mixed w/graft Systemic: 0.1 mg/kg (IV)

Preop: 4 wk Postop: 4 wk Local: 1 dose Systemic: 6 or 12 wk

Urrutia et al. [47]

Rabbit

PLF w/ autograft

Pamidronate

3 mg/kg (IV)

1 Postop dose

Lehman et al. [21]

Rabbit

PLF w/ autograft

Alendronate

200 mg/d (oral)

8 wk

Zou et al. [32]

Pig

Alendronate

10 mg/d (oral)

12 wk

Xue et al. [23]

Pig

Alendronate

10 mg/d (oral)

12 wk

Xue et al. [24]

Pig

Alendronate

10 mg/d (oral)

12 wk

Xue et al. [25]

Pig

ALIF w/ three implant types þ autograft Instrumented PLF w/ autograft ALIF w/ Brantigan cage þ allograft (treated vs. untreated) Instrumented PLF þ ceramic

Alendronate

10 mg/d (oral)

12 wk

Xue et al. [33]

Pig

Alendronate

10 mg/d (oral)

12 wk

Instrumented PLF w/ autograft

8 wk

Number of subjects 8C 8T 11 C 11 T 13 C 13 T 21 C 21 Therapeutic 21 Overdose 21 C 24 Therapeutic 25 Overdose 18 C 19 T 8C 8 Local 8 Systemic 16 C 16 T 21 C 22 T 9C 9T 11 C 11 T 5C 5T 11 11 11 11

C T C T

ovx, ovariectomized model; PLF, posterolateral fusion; w/, with; SQ, subcutaneous injection; C, control; T, treatment; DBM, demineralized bone matrix; IV, intravenous; Preop, preoperative; Postop, postoperative; ALIF, anterior lumbar interbody fusion.

studies commented that fusion masses in treated animals had larger amounts of residual unincorporated bone graft at the fusion site as long as 8 weeks after the fusion procedure [20,27,28]. Takahata et al. [27] showed that treatment with alendronate produced fusion masses containing a significantly higher proportion of cartilage as a percentage of tissue volume. In looking at osteoclast activity, three studies found that the fusion masses of animals exposed to alendronate contained significantly lower numbers of osteoclasts than did that of controls [27–29]. One included article analyzed the effects of bisphosphonate treatment on microstructural indices of the fusion mass. Using micro-CT, Takahata et al. [27] showed that ovariectomized rats treated with alendronate had significantly higher bone volume as a proportion of tissue volume, trabecular connectivity, and trabecular thickness than did untreated controls. This was demonstrated in animals treated for 4 weeks and in those treated for 8 weeks. Three authors investigated the effect of bisphosphonate treatment on biomechanical properties of the fusion mass. In a rabbit model of posterolateral lumbar fusion, subjects treated with pamidronate for 4 weeks before surgery and

4 weeks after surgery had fusion masses with a significantly lower peak tensile load to failure and significantly less stiffness than did controls [30]. Nakao et al. [29] found that ovariectomized rats treated with 8 weeks of alendronate had significantly greater peak load to failure in three point bending but no difference in stiffness. Bransford et al. [31] showed that rabbits treated with a single intraoperative systemic or local dose of zoledronate had significantly less flexion range of motion at the fused level than control animals. However, this study failed to find any significant differences in stiffness of the fused level between groups. Two studies examined the effect of bisphosphonate treatment on the bone/implant interface in porcine models of spine fusion. Zou et al. [32] found that 12 weeks of treatment with alendronate produced a greater amount of tissue ingrowth into interbody devices made of tantalum when compared with untreated controls. In animals fused with carbon fiber cages, alendronate treatment produced no change in bony ingrowth. In a porcine model of instrumented PLF, Xue et al. [33] found a significant increase in the percent of pedicle screw surface area in contact with bone in animals treated with 12 weeks of alendronate. However, this did not

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Table 2 Studies assessing the effect of bisphosphonates on fusion rate as determined by manual palpation and/or radiography Study

Model used

Duration of treatment

Medication

Fusion rate

Method used to assess fusion rate

Takahata et al. [27]

Rat (ovx)

4 or 8 wk

Alendronate

NSD at either time point

Nakao et al. [29]

Rat (ovx)

8 wk

Alendronate

NSD

Gezici et al. [22]

Rat

10 wk

Risedronate

NSD

Sama et al. [28]

Rat

2, 4, or 8 wk

Alendronate

NSD

Huang et al. [20]

Rat

8 wk

Alendronate

Babat et al. [30]

Rabbit

8 wk*

Pamidronate

C 95% T 50%y OD 45%z NSD

Bransford et al. [31]

Rabbit

1 local dose, 6 or 12 wk

Zoledronate

Urrutia et al. [47]

Rabbit

1 dose postoperatively

Pamidronate

NSD between controls and either local or systemic delivery NSD

Fusion was defined as the combination of the absence of motion on palpation by each of the three blinded orthopedic surgeons and the presence of bony continuity between transverse processes on a PA radiograph Fusion was defined by visualization of continuous bony bridge in the intertransverse fusion mass by two blinded observers Manual palpation: fusion defined as the absence of motion on palpation by two blinded observers Radiographic: fusion defined by AP radiographs to which a scoring system was applied by two evaluators; a minimum threshold score was considered fusion Mass scored as fused or not fused by three blinded observers based on an examination of any relative motion at the level of surgery Fusion defined as no palpable motion at the level of surgery, determined by two blinded observers Fusion defined as absolute lack of segmental motion at the level of surgery, determined via manual palpation by two blinded spine surgeons (disagreement was resolved by determination of a third surgeon) Fusion defined as no apparent motion on manual palpation

Lehman et al. [21]

Rabbit

8 wk

Alendronate

NSD

Xue et al. [23]

Pig

12 wk

Alendronate

NSD

Fusion was defined as the combination of the absence of motion on palpation by two blinded observers and the presence of bony continuity between transverse processes on an AP radiograph Manual palpation: fusion defined as the absence of motion on palpation Radiographic: fusion defined by two independent observers based on the presence of a continuous trabecular pattern between transverse processes on PA radiographs X-ray: two independent physicians defined fusion as the presence of continuous bony bridge between transverse processes on either AP or lateral radiographs CT: two independent physicians defined fusion as the presence of continuous bony bridge between transverse processes on sagittal CT images (Continued)

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Table 2 (Continued ) Study

Model used

Duration of treatment

Medication

Fusion rate

Method used to assess fusion rate

Xue et al. [24]

Pig

12 wk

Alendronate

NSD

Xue et al. [25]

Pig

12 wk

Alendronate

NSD

Fusion was defined by two blinded individuals as the presence of a continuous bony bridge crossing the central cavity of the interbody cage either on radiographs or CT scan Fusion defined by two independent observers based on the presence of a continuous bony bridge between adjacent transverse processes on AP and lateral radiographs

ovx, ovariectomized model; NSD, no significant difference; PA, posteroanterior; AP, anteroposterior; C, control; T, treatment dose; OD, overdose; CT, computed tomography. * In the work by Babat et al. [30], animals were treated 4 weeks before fusion and for 4 weeks after fusion. y p5.002. z p!.0001.

correspond to significant increases in the maximum torque tolerated by the screws or to any significant increases in their angular stiffness.

as more than 2 mm vertical migration from baseline on CT scan, was not significantly different between groups. No significant difference in clinical outcome was demonstrated between groups using the Oswestry Disability Index.

The effect of bisphosphonates on spinal fusion in humans

The effect of PTH on spinal fusion

There has been one human study on the effect of bisphosphonates on spine fusion. Nagahama et al. [34] studied 36 osteopenic patients undergoing single-level posterior lumbar interbody fusion, randomized to either 35 mg/wk of alendronate or 1 mg/d of alfacalcidol (vitamin D) for 1 year. Levels were considered fused when there was less than 5 of angular motion on flexion-extension radiographs and bridging bone was visualized through at least one interbody cage on CT reconstruction. Using these criteria, patients receiving alendronate had a significantly higher fusion rate when compared with controls (95% vs. 65%, p5.025) at 1 year after surgery. The incidence of cage subsidence, defined

Four studies investigated the effect of PTH on spinal fusion. All used the 34-amino acid version of human recombinant PTH. Information on the animal model, drug, drug dosage, dosing schedule, and number of subjects used in each study appears in Table 5. All investigations used a posterolateral lumbar fusion model. All studies controlled the amount of bone graft used. All four studies used either manual palpation and radiographic assessment or a combination of the two to assess fusion rate. Using these techniques, one article detected a difference in fusion rate between animals treated with PTH and controls. O’Loughlin et al. [35] defined fusion as the absence

Table 3 Studies on bisphosphonates making a histologic determination of fusion rate and their associated methodologies Study

Model used

Duration of treatment

Medication

Fusion rate

Gezici et al. [22]

Rat

10 wk

Risedronate

Lehman et al. [21]

Rabbit

8 wk

Alendronate

Xue et al. [23]

Pig

12 wk

Alendronate

C 73% T 34% p5.004 C 76% T 45% p5.004 NSD

Xue et al. [24]

Pig

12 wk

Alendronate

NSD

Xue et al. [25]

Pig

12 wk

Alendronate

NSD

C, control; T, treatment; NSD, no significant difference between groups.

Histologic method used to assess fusion rate Fusion defined based on a maximum Emery score of 6 or higher as assigned by two blinded pathologists Fusion defined based on a maximum Emery score of 6 or higher as assigned by two blinded pathologists Fusion defined as the presence of continuous trabecular bone bridging one adjacent transverse process to the next on histologic analysis Fusion defined as the presence of continuous trabecular bone connecting one adjacent vertebral body to the next through the center cavity of the interbody cage Fusion defined as the presence of continuous trabecular bone bridging one adjacent transverse process to the next on histologic analysis

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Table 4 Animal studies evaluating the impact of bisphosphonates on histologic fusion mass quality Study

Model used

Duration of treatment

Medication

Histologic measures evaluated

Huang et al. [20]

Rat

8 wk

Alendronate (two dosage levels)

Percent area of fusion mass occupied by bone or marrow elements

Xue et al. [23]

Pig

12 wk

Alendronate

Percentage of bone, marrow, cartilage, and fibrous tissue within the fusion mass Proportion of woven bone within the fusion mass

Xue et al. [24]

Pig

12 wk

Alendronate

Xue et al. [25]

Pig

12 wk

Alendronate

Takahata et al. [27]

Rat (ovx)

4 or 8 wk

Alendronate

Percentage of bone volume, bone marrow volume, and fibrous tissue volume in each fusion mass Percentage of bone marrow, ceramic bone graft, and fibrous tissue in each fusion mass Cartilage volume/total tissue volume, osteoclast number, and osteoclast surface area

Nakao et al. [29]

Rat (ovx)

8 wk

Alendronate

Osteoclast number

Sama et al. [28]

Rat

2, 4, or 6 wk

Alendronate (two dosage levels)

Area fraction of unremodeled bone, osteoclast number, percent osteoblasts per bone surface

Findings Fusion masses in overdose group had significantly higher proportion of bone (p5.01) and lower proportion of marrow (p!.001) as compared with controls Fusion masses in the therapeutic dose group had a significantly lower proportion of marrow elements (p!.001) Treated animals had a higher percentage of fibrous tissue within fusion masses (p!.05) Treated animals had a higher proportion of woven bone than controls (p!.001) NSD between T and C groups

NSD between T and C groups

At 4-wk time point: decreased osteoclast number and osteoclast surface area in treated animals as compared with controls At 8-wk time point: significantly greater cartilage volume/total tissue volume Osteoclast number was significantly lower in the treated subjects Authors also made a descriptive statement that bone neogenesis was excellent in the treated group as compared with controls but did not provide quantitative statistical analysis Overdose group: Greater area fraction of unremodeled bone at 4 wk (p!.001) and 6 wk (p!.001) - Fewer osteoclasts (p!.01) - Lower percent osteoblasts per bone surface (p!.05) at all time points Therapeutic dose group: - Greater area fraction of unremodeled bone at 6 wk (p!.001) - Lower number of osteoclasts at 4 and 6 wk (p!.01) - No differences in the percent osteoblasts per bone surface area were observed -

ovx, ovariectomized model; T, treatment; C, control; NSD, no significant difference between groups.

of motion on manual palpation by three blinded observers. Specimens were determined to be fused when at least two of the observers agreed on the absence of motion. In this rabbit model of posterolateral lumbar fusion, rabbits treated

with 6 weeks of 10 mg/kg/d of PTH had a fusion rate of 81% compared with a fusion rate of 30% in untreated controls (p!.01). One study made an additional determination of fusion rate based on histology using the Emery score

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Table 5 Demographic information on studies evaluating the effect of PTH on spine fusion Study

Animal

Model

Drug

Dose

Duration

Number of subjects

Abe et al. [37]

Rat

PLF w/ autograft L4/L5

PTH (1–34)

40 mg/kg/d (SQ)

14, 28, or 42 d

Lawrence et al. [48]

Rat

PLF w/ autograft L4/L5

PTH (1–34)

20 mg/kg/d (SQ)

6 wk

O’Loughlin et al. [35]

Rabbit

PLF w/ autograft L5/L6

PTH (1–34)

10 mg/kg/d (SQ)

6 wk

Lehman et al. [36]

Rabbit

PLF w/ autograft L5/L6

PTH (1–34)

10 mg/kg/d (SQ)

8 wk

21 21 27 29 22 22 14 15

C T C T C T C T

PTH, parathyroid hormone; PLF, posterolateral fusion; w/, with; SQ, subcutaneous injection; C, control; T, treatment.

[36]. In this article, fusion masses with an average Emery score of 5.5 or greater were considered fused. Using this criteria, Lehman et al. found that rats treated with 8 weeks of 10 mg/kg/d of PTH had a fusion rate of 86.7% compared with 50% in untreated controls (p5.033). Three studies on PTH assessed its effect on the histologic, microstructural, or biomechanical properties of the fusion mass. Two articles examined the histologic characteristics of the fusion mass without using them to define fusion. Abe et al. [37] found that at both 4 and 6 weeks of treatment with 40 mg/kg/d of PTH, subjects had a significantly higher mineral apposition rate when compared with controls. Treated animals also had a significantly greater mineralized surface area and osteoclast surface area as proportions of bone surface area. O’Loughlin et al. [35] found that animals exposed to 10 mg/kg/d of PTH for 6 weeks had a significantly higher percentage of bone tissue and a significantly lower percentage of fibrous tissue than did controls. The study also found a significantly higher number of osteoclasts per high-power field and a significantly higher number of osteoblasts in apposition to osteoid within the fusion mass of treated subjects as compared with controls. One study examined the effect of PTH on the microstructural properties of fusion masses in a rodent model of posterolateral lumbar fusion [37]. Using micro-CT analysis, the authors found that animals treated with 40 mg/kg/d of PTH had a significantly higher proportion of bone tissue volume and trabecular number at all time points. Trabecular thickness was also significantly greater at the 2- and 6week time points in treated animals. A single article evaluated the biomechanical properties of fusion masses in a rabbit posterolateral lumbar fusion model in the context of exposure to PTH [36]. Rabbits receiving 10 mg/kg/d of PTH for 8 weeks exhibited no significant differences in triplanar range of motion during loading cycles on the fused segment.

Discussion The biology of spinal fusion is a complex process that requires de novo bone formation and remodeling by the osteoblast/osteoclast complex. Therapies for osteoporosis

target this complex, altering its function. It is therefore reasonable to question whether these drugs affect outcomes in spinal fusion. The aim of this systematic review was to evaluate the available data regarding the impact of bisphosphonates and PTH on spinal arthrodesis. It should be emphasized that at the time of our search, the literature contained only one trial of these medications in humans, with nearly all data coming from animal models. In animals, data regarding the effect of bisphosphonates on fusion rate are mixed and appears to be dependent on the methodology used to define fusion. Most articles that used the methods of manual palpation and/or radiographic evaluation did not find a statistically significant difference in fusion rate, whereas studies that used a histologic definition of fusion [21,22] found that bisphosphonates decreased the fusion rate. With regard to fusion mass quality, bisphosphonate treatment appears to slow the process of remodeling that is necessary for incorporation of bone graft during spine fusion. In the available literature, the fusion masses of treated animals tended to have a higher percentage of immature or unremodeled bone, a higher percentage of cartilage, and reduced osteoclastic and osteoblastic activities [20,23,27,28]. These findings are logical given the mechanism of action of bisphosphonates and the crucial role of the osteoclast in bone graft incorporation and remodeling. The ultimate effect of this delay in remodeling on the biomechanical strength of the fusion mass is unclear, with several studies yielding conflicting results using different methods of measurement [29–31]. In animals, bisphosphonate treatment appears to increase osseointegration of spinal instrumentation [32,33], although this has not yet been shown to improve the biomechanical strength of the bone/implant interface. Overall, the available data suggest that PTH can improve fusion rates in animal models at early time points (4–8 weeks) [35,36]. The anabolic effect of PTH speeds the formation of a histologically mature fusion mass having a greater proportion of mineralized tissue and a more robust microstructure [35,37]. It is unclear whether these changes in fusion quality translate to a fusion mass with greater biomechanical strength as no study has performed true biomechanical analysis. Currently, all available data come from rodent and rabbit models of spine fusion. It is unknown

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whether these effects of PTH would also be present in human spine fusion, which has a different biologic and biomechanical environment. Given the encouraging results seen in animals, human studies should be undertaken to evaluate the potential for PTH to augment spine fusion. The primary limitation of the present review is its dependence on information that has been gathered nearly exclusively from animal models. At the time of the literature search, only one human trial of 36 patients has been conducted with regard to the effects of these medications on spine fusion [34]. Direct application of the conclusions of these animal studies to human spine fusion should be avoided. Although the reviewed animal models have been well characterized and extensively studied, they lack certain biomechanical and biologic features of human spine fusion in the osteoporotic population. The rodent, porcine, and rabbit models used previously are quadrupedal spine models, in contrast to the human bipedal spine. The differences between the quadruped and biped spine, particularly as they relate to the paravertebral musculature and the intervertebral disc, have been well documented [38–40]. It is likely that similar discrepancies exist between these two spinal configurations with regard to the incorporation of bone graft in spine fusion. In addition, most experiments involving bisphosphonates and all the studies involving PTH were performed in noninstrumented models of fusion. In modern clinical practice, almost all lumbar fusions now involve some form of instrumentation. This is an important distinction, as the increased rigidity of instrumented fusion certainly influences the process of fusion [41,42] and could confound the pharmacologic effect of the medications in question. Other aspects of the experimental design of the present animal studies further limit their clinical applicability. Only two studies used estrogen-deficient animals to model osteoporosis [27,29]. As the hyper-resorptive state of osteoporosis may have implications for the way that bisphosphonates and PTH affect the biology of spine fusion, it would be prudent to use models of osteoporosis in all future studies. Furthermore, only one study began administering drug in advance of the spine fusion procedure [30]. This does not mimic the biological environment often seen by surgeons who perform fusion on a patient who has known osteoporosis and a history of treatment. This design is particularly relevant in the case of bisphosphonate use, given that these drugs remain bound to the skeleton for long periods of time. Animals (and patients) treated with bisphosphonates before surgery will have active drug present in their autograft, further affecting the resorption and incorporation of graft into the fusion mass. Pretreatment with PTH also has the potential to impact the fusion mass by improving the quantity and quality of bone stock at the site of fusion. Future studies should use pretreatment to better mimic the clinical scenario in question. The lone human trial on the effect of bisphosphonates on spine fusion demonstrated a higher fusion rate in treated

patients 1 year after surgery, without any improvement in clinical outcome [34]. These findings suggest a beneficial effect of alendronate in instrumented interbody fusion. The study was limited by a short duration of follow-up, the use of only one clinical outcome measure, and a small sample size in which no patients suffered instrumentation failure or required reoperation. Furthermore, the assessment of fusion rate relied exclusively on radiographic measures, which have debatable reliability [43–45]. Although this study presents new and useful information about the effect of bisphosphonates on spine fusion, it is important to note that its findings are specific to interbody procedures. The healing environment in the interbody region differs from that of the posterolateral spine as each are subject to different loading forces and have differing amounts of cancellous bone [46]. It is possible that alendronate use is advantageous in the compressible environment of interbody fusion; however, this effect may not transfer to fusion of the posterior elements only. Human studies evaluating this effect on posterolateral fusion are a necessity given the widespread use of this method of arthrodesis. In conclusion, the existing animal data on the effect of bisphosphonate medications on spine fusion are conflicting but indicates that treatment delays remodeling of the fusion mass. The single human study conducted suggests improvement in radiographic parameters with treatment but contained limited clinical outcome data. Although no trials of PTH in humans have been performed, the current animal literature provides evidence for a beneficial effect on spine fusion. In the absence of conclusive human data relating to spine fusion, we recommend the continuation or initiation of these therapies in patients based on their indication for the treatment of osteoporosis, without regard for a recent or impending spine fusion procedure. However, on the basis of preclinical data, we believe that anabolic agents may offer an advantage over antiresorptive medications in osteoporotic patients undergoing spine fusion. Future human studies in this area are of great importance and have the potential to change clinical practice.

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