Alendronate Induced Stress Fractures

Alendronate induced stress fractures

Sujit Kumar Tripathy, M.S., DNB, MNAMS, Dip SICOT, MCH Student (Ortho) Teeside University, UK

Saumitra Goyal, Postgraduate student (Orthopaedics), KMC, Manipal

Introduction

• Alendronate, an inhibitor of bone resorption, was the first oral medication widely accepted for use in treatment of osteoporosis associated with high burden of low-energy fractures of the proximal femur, vertebrae, and distal radius.
• However, concerns have been raised about potential over-suppression of bone turnover during long-term use and increased risk of fragility (stress) fractures.

 

Bone metabolism and fragility fractures

• Bone metabolism is characterized by two opposing activities

1. Bone resorption consists of the dissolution of bone mineral and catabolism of the bone matrix constituents by osteoclasts, leading to formation of a resorptive cavity and release of bone matrix components. Osteoclasts simultaneously accomplish mineral dissolution and matrix digestion.
2. Bone formation where osteoblasts synthesize bone matrix, fills up the resorption cavity and undergoes rapid primary mineralization followed by the slow long-term secondary mineralization.

This continues in a cyclical fashion all throughout life although rate of bone turn over changes with age, endogenous hormone levels and various drugs.

 

• Remodeling responds to functional demands of the mechanical loading. All bones have a tensile and a compressive surface and the underlying trabeculae are laid down during the process of bone remodeling in accordance to the Wollf’s law.
• These processes also control the reshaping or replacement of bone following injuries like fractures but also micro-damage, which occurs during normal activity.
• Bone micro-damage is characterized by failure of fiber-matrix bonding and disruption of mineral-collagen aggregate creating micro crack. These cracks are a result of the stress state during normal mechanical loading of the bone.
• With each remodeling cycle, bone mass is decreased a little bit more. This in turn increases mechanical strain on the remaining bone, causing a greater accumulation of damage that must be repaired, which is accomplished by the bone turn over cycle in normal bone.
• Accumulation of micro-damage in the bone subsequent to cyclic loading leads to mechanical failure of the bone. Over many remodeling periods, the gradual decline in bone mass and equally gradual accumulation of micro-damage will lead to a greater fragility of the bone.
• In osteoporotic bones bone resorption continues and the formation rates decrease causing more severe deterioration of bone micro architecture and a more severe decrease in bone strength. Two resorption cavities on the opposite side of a trabecula, trigger stress risers that result in the local weakening of the trabecula and even functional loading forces overwhelms the mechanical properties of the bone and lead to stress or fragility fracture.
• Fragility-type fractures are defined as any fracture of the distal radius, proximal femur, vertebral body or proximal humerus that had occurred with minimal trauma (no greater than the trauma that would be experienced with a fall on a level surface while walking or standing).

 

What is Alendronate (4-amino-I-hydroxybutylidene- 1, 1-biphosphonic acid)?

• Bisphosphonates; prototype Alendronate, are carbon-substituted pyrophosphate (PCP) analogues which are potent inhibitors of bone resorption. Like pyrophosphate, bisphosphonates bind to hydroxyapatite and as a result are taken up by bone.
• Proposed mechanisms of action include

1. Cytotoxic or metabolic injury of mature osteoclasts,
2. Inhibition of osteoclast attachment to bone,
3. Inhibition of osteoclast differentiation or recruitment
4. Interference with osteoclast structural features (cytoskeleton) necessary for bone resorption.

 

 

Effects of Bisphosphonate on bone

• Alendronate binds to sites of bone resorption, is locally released by acidification, which increases its local concentration under the osteoclasts and interferes with bone resorption and ruffled border formation.
• Bisphosphonates inhibit the activity of mature osteoclasts which undergo apoptosis as a result of inhibition of farnesyl diphosphate synthase, an enzyme in the mevalonate pathway that is important in the maintenance of the cytoskeleton and for cell survival.
• Bone resorption decreases significantly after 3 weeks of the anti-resorptive treatment and attains the nadir after 3–6 months of treatment and then remains stable (because of its interruption in normal bone turnover cycle). This decrease is followed by a decrease in the bone formation markers (significant decrease after 6 weeks, nadir after 6–12 months).
• Although bisphosphonates are excreted by the kidneys, the amount remaining in the body may attach to the osteoid tissue for decades. They have a strong affinity to bone, are accumulated in bone tissue, not metabolized and are released from the bone very slowly with estimated terminal half-lives of 1–10 years.
• The presence of bisphosphonates on inactive bone surfaces provides a reservoir of drug that can inhibit future generations of osteoclasts. This affinity for bone (and therefore the half-life) varies among different types and is the greatest, in order, for zoledronate, alendronate, ibandronate and risedronate.
• Bisphosphonates are compounds that, depending on dosage, can reduce bone turnover to nearly zero, allowing virtually no repair of micro damage that may accumulate as the result of normal activity. Thus, long term use of bisphosphonates may allow studies to test the hypothesis that failure to repair micro cracks can result in the accumulation of damage and eventual fracture.

Literature review

• Odvina et al and Goh et al have reported low-energy fractures in patients after prolonged alendronate therapy. The proximal femoral shaft (subtrochanteric region) has been reported as the most common site.
• Odvina et al reported on 9 patients who had sustained spontaneous, nontraumatic, nonpathologic fractures while receiving prolonged alendronate therapy (longer than 3 years). Fracture sites included the pubic ramus, femoral shaft, ischium, rib, and sacrum. They reported following histomorphometric evidences of severely suppressed bone turnover: bone surface devoid of cellular elements, reduced bone formation rate and severely impaired matrix formation.
• Randomized trials have not demonstrated beneficial effect of aledronate beyond 5 years.
• Curtis et al found that discontinuation of alendronate after three years of use was not associated with an increased risk of hip fractures during the next year compared with those who continued with treatment.
• Available data suggests that there is no negative effect on fracture risk after 5 years of alendronate therapy as evidenced by vertebra and non-vertebra fracture measured by radiographs (exception: a group of women who had vertebra and femur neck fracture due to osteoporosis, evidenced by DEXA <2.5 and they were on alendronate treatment for  five years).

 

Conclusion

• Alendronate has been widely and successfully used to treat osteoclast-mediated metabolic bone diseases, such as osteoporosis.
• It has been proved effective in improving all clinical measures of osteoporosis, including increasing bone mineral density, reducing laboratory markers of bone turnover, and reducing the number of fractures in the spine and long bones.
• Alendronate targets osteoclasts by binding to the inorganic component of bone. Bone resorption and remodeling rates are diminished as a result of osteoclast death.
• Reduced bone resorption is followed by reduced bone formation and resorption cavities trigger stress risers to routine physiological activities.
• Severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and also delayed healing of nontraumatic, nonpathologic fractures.
• No beneficial effect of alendronate has been demonstrated beyond five years.

 

References:

1. Sayed-Noor AS, Kadum BK, Sjoden GO.  Bisphosphonate-induced femoral fragility fractures: What do we know? Orthopedic Research and Reviews 2010:2 27–34
2. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294–1301.
3. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: A caution. J Bone Joint Surg Br. 2007;89:349–353.

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