Fracture consolidation and osteoporosis






Jean-Marc FÉRON, MD, PhD
Head of the Orthopedic and Trauma Department
Saint Antoine Academic Hospital
Université Pierre et Marie Curie
(UPMC), Sorbonne University
Paris, FrAnCe

Fracture consolidation and osteoporosis


by J. M. Féron, France



Bone differs from other tissues in its capacity to self-repair after a fracture. The role of the orthopedic surgeon is to reduce the bone fragments anatomically, stabilize the fracture to allow healing without malunion, and thus restore function. The healing process is a cascade of events, mainly influenced by the mechanical fracture fixation stability and the biological environment, summarized as the “diamond concept.” Depending on various factors, bony union occurs either by primary or secondary healing. Basic knowledge of fracture healing is a prerequisite to understanding how the repair of fragility fractures can be improved. The osteoporotic elderly population presents a higher risk of nonunion or delayed union, which leads to increased morbidity and economic burden. Antiosteoporotic drugs target either reduced bone remodeling or stimulate bone construction in order to increase bone strength and prevent fractures. It is important to know their potential interactions on the fracture healing process and to assess their ability to promote bone healing. Most preclinical studies, largely involving osteoporotic rodent models, have demonstrated a stimulation of fracture healing by bone-forming agents; there is no evidence of any deleterious effect on the early stage of fracture healing by antiresorptive drugs. In humans, several case reports and well-designed clinical trials seem to confirm the potential beneficial effects of bone-forming agents on fracture repair. More studies are needed to evaluate this systemic approach of enhancing fracture repair, especially in people diagnosed with osteoporosis.

Medicographia. 2014;36:156-162 (see French abstract on page 162)



Bone differs from other tissues in its capacity to self-repair after a fracture. The role of the orthopedic surgeon is to stabilize the fracture with bone contact and restore the normal anatomy. The fracture healing process is under the control of mechanical and biological factors summarized in the “diamond concept.” Basic knowledge of the healing process is a prerequisite to understanding how the repair of fragility fractures in older osteoporotic patients can be improved.

Antiosteoporotic drugs have been shown either to reduce bone remodeling or stimulate bone construction, thus increasing bone strength and preventing fractures. Their interactions in the fracture healing process have mainly been studied in animal models. Despite there being few clinical studies, there exists some encouraging evidence for systemic stimulation of bone repair in the future, either by shortening the healing time of fractures or preventing nonunion in high-risk populations.

Mechanisms of normal fracture repair

Bone, unlike other tissues, has the capacity to self-repair after a fracture without leaving a scar.1 Once the continuity of the bone and its mechanical properties are restored, the bone structure recovers its pre-injury state. Fracture healing is a complex process involving biological factors and mechanical principles. The stability of the fracture, depending on the method of fixation chosen by the surgeon, determines the type of bony union.2 Bone union occurs either by primary or secondary healing.3

Primary fracture healing, or direct bony union, occurs when there is no motion at the fracture site, and is usually achieved after a surgical procedure: open anatomical reduction with very rigid internal fixation.4 Direct contact of compact bone is required and the fracture gap should be less than 200 μm, so that cutting cones are formed at the end of the osteons closest to the fracture site. This “contact healing” involves osteoclasts, which cross the fracture line and create small cavities. These cavities are filled by new bone generated by osteoblasts from the surrounding mesenchymal cells. Bony union and haversian remodeling occur simultaneously. This is a slow process, quite similar to intramembranous ossification during fetal skeletogenesis and to normal bone remodeling. The fracture heals directly without the formation of a periosteal callus (Figure 1). In the same mechanical and anatomical conditions, the process differs when the gap is wider, but still less than 1 mm. In this “gap healing” process, the gap is primarily filled with lamellar bone, which is mechanically weak after 4 to 8 weeks and is followed by remodeling, which starts as the “contact healing” cascade takes place.

Secondary fracture healing, or indirect bony union, is the most common process through which bone union occurs after a fracture. This indirect healing does not require an anatomical reduction of the fracture or highly rigid mechanical conditions. The biological response under loading is the formation of an external callus bridging the fracture gap, with the fracture considered healed when bone continuity is visible on x-ray. Indirect bone healing is characteristic in nonoperative fracture treatment and in elastic fixation, preserving some micromotion at the fracture level, such as intramedullary nailing, external fixation, or plate fixation in complex and comminuted fractures. The process recapitulates the steps of the endochondral ossification during the fetal period.5

The histological morphology of bone after fracture was first described in 1930 by Ham and the cellular mechanism later emphasized by McKibbin.6 The improved understanding of bone biology over the last decades has increased the knowledge of the molecular control of cellular events.7 The healing process involves a combination of intramembranous ossification and endochondral ossification, similar to bone formation during osteogenesis. The healing process has been characterized by four successive phases, while in reality it appears that they may occur at different rates, at different sites, and sometimes simultaneously.

Fracture repair follows a characteristic course, which can be divided into three partially overlapping phases: the inflammatory, repair, and remodeling phases.8 The first two phases last 10 to 18 weeks and correspond to the restoration of bone continuity and mechanical properties to allow full weight bearing. The last phase takes months to years and can be considered a gradual adaptation of the restored bone to the usual strains of life.



Figure 1. Rigid plate fixation and primary healing of a combined tibia and fibula fracture.

A. Preoperative x-ray. B. X-ray 1 year postsurgery: rigid plate fixation and primary healing.



Inflammatory phase
Hematoma and inflammation are the immediate reactions to fracture: bleeding occurs from the bone and the surrounding soft tissues and the microvascular disruption leads to hypoxia and bone necrosis. The hematoma coagulates around the bone extremities and within the medulla, forming a template for callus formation. The fracture hematoma houses blood-derived inflammatory cells, which release cytokines and initiate the inflammatory response: increased blood flow, increased vessel permeability, and increased cell migration.9 Osteoclasts are activated to resorb bone debris, and vascular proliferation provides stem cells, which differentiate into cells with osteogenic potential based upon the mechanical environment and signaling molecules. This inflammatory response peaks within 24 hours and is complete after 7 days. A tissue, called callus, forms at the fracture site and stiffens as it calcifies.


Figure 2
Figure 2. Locked nail fixation of a tibial fracture.

A. Postoperative x-ray. B. Secondary bone healing at 4 months with a callus formation.



Repair phase
The nature of the repair phase is dependent on mechanical and anatomical conditions in the fracture healing zone (primary or secondary healing). In the secondary healing process, the fracture repair has been classically divided into the formation of soft callus, which subsequently calcifies to form the hard callus. During the soft callus formation (3-4 weeks) the clot is invaded by a fibrin-rich granulation tissue. Within this tissue, an endochondral formation develops between the bone extremities and external to the periosteum. This chondroid cartilaginous matrix rich in proteoglycans and type 2 collagen is replaced by an osteoid matrix rich in type 1 collagen. The ossified cartilage is replaced progressively by woven bone. The soft callus enveloping the bone extremities becomes more solid and mechanically rigid. The hard callus formation (3-4 months) is characterized by an intramembranous ossification occurring in the subperiosteal area adjacent to the distal and proximal ends of the fracture forming the peripheral hard callus (Figure 2). The inner layer of the periosteum contains osteoblasts, which synthesize a matrix rich in type 1 collagen and directly generates calcified tissue.10 This final central bridging by woven bone provides the fracture with a semi-rigid structure, allowing weight bearing and restoring the function of the limb. At this stage the woven bone is identical to the secondary spongiosa of the growth plate, and the fracture is considered healed.

Remodeling phase
Once the fracture has been bridged by the callus, the process of fracture repair slowly replacing the new woven bone with lamellar bone continues. The remodeling results in a balanced resorption of the hard callus by osteoclasts and lamellar bone deposition by the osteoblasts. This last phase is initiated as early as the first month, and it takes years to achieve the reconstruction of the original bone structure.

The “diamond concept” of normal fracture healing

The “diamond concept,” described by Giannoudis, is a requirement for successful bone healing.11 The fundamental constituents of bone healing are: the osteogenic cells that initiate repair, an osteoconductive scaffold upon which new bone can be created, and osteoinductive growth factors, like bone morphogenetic protein, that differentiate the stem cells along the bone repair pathway. Mechanical stability is a fourth crucial element which must be given the same importance.

This conceptual framework is completed by two of the most significant parameters for the healing process: vascularity at the site of the fracture and the biology of the host (Figure 3).12 The progression of fracture healing can be compromised by many physiological, pathological, or environmental factors. A recent large case-control study has shown that factors like diabetes, nonsteroidal anti-inflammatory use, or high-energy trauma are more likely to results in fracture-healing complications, regardless of fracture site.13 Aging, smoking, and inflammatory conditions also increase the risk of delayed union or nonunion (Figure 4).14,15


Figure 3
Figure 3. The “diamond concept” of bone fracture healing interactions.

Adapted from reference 12: Giannoudis et al. Injury. 2008;39(suppl 2):S5-S8.
© 2008, Elsevier Ltd.


Fracture healing, osteoporosis, and aging

Osteoporotic bone differs from normal bone in its reduced bone mass and deterioration of its architecture, leading to bone fragility and an increased fracture risk. This is a consequence of the imbalance between bone formation and bone remodeling. Osteoporosis is potentially harmful for fracture treatment: the compromised bone strength affects anchorage of the implants and, at the fracture site, the impaired bone ingrowths and late remodeling could impair the strength of the callus and bony union.16 Few studies have investigated the effects of osteoporosis itself on the bone healing process. Fracture healing has been assumed to be the same in osteoporotic bone and normal bone.

Animal studies have been conducted on ovariectomized rodent animal models with a tibia or femur osteotomy.17 Despite some contradictory results, more studies support a delay in ossification, a decrease of 20% to 40% in callus area, and a reduction of around 20% in bone mineral density. Mechanical properties of the callus were also disrupted, with decreased strength, decreased peak failure load, and decreased bending stiffness. The architecture was modified with thinning and disruption of the trabeculae and a decrease in connectivity.18

Clinical data are even more controversial. The failure rates of fixation in patients with osteoporosis range from 10% to 25%.19 Despite significant effects in several clinical studies, there is so far no high level of evidence that osteoporosis, per se, increases the incidence of fracture nonunion.20,21 Cohorts of patients are heterogeneous, and randomized studies comparing osteoporotic patients with non-osteoporotic patients are missing.

Osteoporosis is closely linked with aging. Fracture healing in the elderly is compromised by the decline in capacity of bone formation.14 The loss of osteoblasts in the aging skeleton has been attributed to a decrease in the number of mesenchymal stem cells and their ability to differentiate in progenitors toward the osteoblastic lineage.22 Due to the augmentation of life expectancy, the absolute number of fragility fractures and its corollary, the absolute number of delayed union or nonunion, increase and the consequences are an augmentation of the mortality and morbidity in this population. The main determinants for deficient fracture healing can be divided into biological and surgical factors (Figure 4).19

The treatment of fragility fractures in the elderly remains challenging for the orthopedic surgeon. The poor quality of bone and frequent fracture comminution make fixation of osteoporotic fractures difficult, despite the development of new fixation devices like locked plating or locked intramedullary nailing, both having revolutionized fracture fixation in weak bone.23 Augmentation with cement or bone substitutes may fill the bone void or enhance the strength of the fixation. As in hip fractures, where the indications of arthroplasty have been well described for a long time, some complex epiphyseal fractures (shoulder, elbow, knee), may benefit from primary prosthetic replacement. This option of replacement, instead of fixation, in comminuted articular fractures of the shoulder, the knee, or the elbow, has faster and better functional results in very elderly people, compared with a mechanically poor fracture fixation.24


Figure 4
Figure 4. Factors for successful fracture healing.

Local stimulation of fracture healing

The mechanical stability of fixation and preservation of the environment, without adding injury to soft tissues (muscles, vessels) are minimal requirements for successful fracture healing. Nevertheless, 5% to 10% of all fractures are complicated by delayed union or nonunion healing. Autogenous bone grafting, as an optimization of the biological milieu, was for years the “gold standard” in the treatment for healing complications (Figure 5, page 160).

Over the past decades, new local interventions have been developed to stimulate or accelerate bone union. Most physical stimulation therapies, such as ultrasound, electrical or electromagnetic fields, and extra corporeal shockwave, seem to stimulate the healing process25 despite the heterogeneity of the clinical studies. Different local biological stimulations have demonstrated their potential to augment the bone regeneration process: autologous mesenchymal stem cell injections from bone marrow aspiration and centrifugation26 or applications of osteoinductive proteins27,28; the next step will be local delivery by gene therapy.29


Figure 5
Figure 5. Complicated intertrochanteric hip fracture in an osteoporotic postmenopausal woman.

A. Postoperative x-ray. B. Nonunion at 9 months and mechanical plate failure. C. Revision surgery with locked nail and autogenous bone graft. D. Healing 3 months later.


Systemic stimulation of fracture healing

Antiosteoporotic drugs have been shown either to reduce bone remodeling or stimulate bone construction in order to prevent fractures and to increase bone strength. The different classes of drugs, antiresorptive, bone-forming, or dual effect agents, have been investigated in preclinical and clinical studies to evaluate how they could influence the early stages of fracture healing. So far, there is no evidence that any antiosteoporosis treatment has negative effects on initial union of fractures in animal models30,31; however, these investigations were conducted in the setting of an indirect healing process. recently in a rodent model of rigid compression plate fixation of a tibial osteotomy, an inhibitory effect of bisphosphonates has been shown on primary healing.32 The clinical evidence of the current and new osteoporosis treatment are reviewed below.

Antiresorptive agents
Bisphosphonates are the most widely used medications to treat osteoporosis. Various studies have demonstrated no increased risk of nonunion or of deleterious effect on fracture healing compared with a control group, independent of the postfracture timing of administration of zoledronic acid or risedronate in intertrochanteric hip fracture or risedronate in distal radius fractures.33 The same results were observed with denosumab, a receptor activator of nuclear factor kappa-B ligand (rAnKL) inhibitor, in the posthoc analysis of a phase 2 clinical trial.34

Bone-forming agents
The impact of parathyroid hormone (PTH) peptides on bone repair has strong evidence in preclinical studies and there is a growing number of cases reporting off-label use in complex situations of impaired healing, suggesting a positive stimulation of bone repair.35 Two recent clinical randomized control trials have investigated the potential of accelerated healing of osteoporotic fractures. In postmenopausal women sustaining a distal radius fracture treated nonoperatively, the median time to radiological healing of the fracture was significantly shortened with 20 μg daily of PTH (1-34) compared with the placebo group.36 Another study compared elderly osteoporotic patients with a pubic fracture: the group treated with 100 g daily of PTH (1-84) had a shorter radiological healing time as well as a better functional improvement compared with the control group.37

Dual-effect agents
Strontium ranelate was found to stimulate bone formation and inhibit bone resorption.38 Most preclinical data support the concept of improved fracture healing and better osseointegration of implants with strontium ranelate.30 evidence from case reports suggest that strontium ranelate has a potentially direct benefit on the fracture healing process. Bone union has been reported in different cases of delayed union or nonunion. 39,40

Strontium ranelate has been reported to have a positive bone anabolic effect on unhealed atypical femoral fractures associated with chronic bisphosphonate use, with a quick increase in bone-formation markers observed following treatment initiation and a cure of the fracture within a few months.41,42

Future anabolic agents
Inhibitors of Wnt signaling proteins, sclerostin and Dikkopf-1 (DKK1), present potential therapeutic options to enhance osteoblastic bone formation.43 To date, only preclinical studies have demonstrated the effects of these antibodies in accelerating bone healing. A clinical phase 2 trial is ongoing with sclerostin antibodies in patients with a tibia fracture or an intertrochanteric hip fracture.

Calcilytic drugs represent a new class of bone-forming drugs. Acting as antagonists of a calcium-sensing receptor (CaSr) in the parathyroid cells, they stimulate the endogenous release of PTH and increase bone formation markers. A study in a phase 2 clinical trial of distal radius fractures has not demonstrated any significant radiological or clinical effect of ronacaleret, a CaSr antagonist, on fracture healing.44

Conclusion

The number of osteoporotic fractures is increasing, especially among the elderly population. Fracture treatment in elderly osteoporotic patients remains challenging. Fracture healing is often compromised, both by a high rate of fixation failure, due to weak bones, and the biological consequences of aging and comorbidities on the bone repair process. To date, impaired healing is treated by mechanical improvement in bone fixation and local biological stimulation by autogenous bone graft, or more recently, “osteobiologics.” With the growing number of antiosteoporotic drugs to prevent fracture and increase bone quality, it was a priority to investigate their impact on the fracture healing process.

The evidence for the effects of antiosteoporotic drugs on fracture healing is rather positive. The concerns for potentially detrimental consequences of such therapeutics on the fracture repair process seem to be overwhelmed by preclinical and clinical data. Following a fragility fracture, there is no reason to delay a preventive antiosteoporotic treatment till the union of the fracture, except perhaps in the case of a very rigidly fixed fracture requiring direct bone union. There is promising experimental and clinical evidence for possible enhancement of the bone repair process via a systemic agent. Further well-designed studies in humans are necessary to accumulate more evidence on the positive effects of such agents and to translate this knowledge into valid therapeutic applications.

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Keywords: antiosteoporotic drug; bone repair; delayed union; fracture; fracture healing; nonunion; osteoporosis