Bone Health of the Runner: Metabolic Workup and Impact on Fracture Risk


Bone stress injuries (BSIs) represent an overuse form of injury resulting from the inability of bone to withstand repetitive loading. BSI may impact the runner's ability to continue sport participation in the short term but can also create long-term disability with the potential for recurrent injuries. During running, the skeleton is exposed to mechanical loading, resulting in deformation of bone. The amount of deformation is dependent on the load magnitude and the ability of the bone to resist strain. If the magnitude of bone strain exceeds a certain threshold, microscopic damage can accumulate. BSI is a continuum of pathology, from microscopic damage, commonly referred to as stress reaction, progressing to stress fracture at the most extreme end of the spectrum. Unrecognized stress fracture can progress to a full fracture that may require surgical management and associated morbidity.

Epidemiology of BSI

Given the repetitive skeletal loading required in long distance running, it is not surprising that BSI is a relatively frequent injury experienced among runners. The incidence of BSI varies based on age and sex. Recent prospective data suggest that the annual incidence of BSI among collegiate cross-country and track-and-field runners of both sexes may reach 20%. In a recent study evaluating the epidemiology of BSI among NCAA collegiate athletes participating in 25 sports over a 10 year period (2004–05 through 2013–14), the first and third highest incidences of BSI occurred in female athletes participating in cross-country and outdoor track, with 28.6 and 22.3 BSI per 100,000 athlete exposures (AEs), respectively. The men's sport with the highest stress fracture rate was cross-country (16.1 per 100,000 AEs). In a prospective study of adolescent runners, the annual incidence of BSI was 5.4% among female runners and 4.0% among males. A separate study evaluating BSI incidence by AE among high school athletes identified girls' cross-country as the highest (10.6 per 100,000 AEs) and boys as the third highest (5.4 per 100,000 AEs). One report in track-and-field and cross-country athletes documented 10.3%–12.6% of those who have a history of BSI sustained a second BSI within 2 years.

BSI Risk Factors

Bone strain is dependent on the interaction between load applied to bone and the bone's ability to resist mechanical deformation. As such, risk factors for BSI can be divided into two main categories: biological factors impacting the bone's ability to resist strain and biomechanical factors that affect the load applied to the skeleton.

Biological Risk Factors for BSI

Biological risk factors for BSI may be both innate and acquired. Familial and twin studies have estimated that as much as 60%–80% of the variance in peak bone mass can be attributed to genetic factors; specific genetic loci associated with bone mineral density (BMD) and others associated directly with fracture risk have been identified. Additionally, acquired factors and exposures can contribute to BSI risk. Medication exposures including glucocorticoids, along with some antiepileptic medications, anticoagulants, antidepressants, and antacids can negatively affect bone health (see Table 15.1 ). Nutritional deficiencies in calcium and vitamin D are risk factors for BSI. Systemic illnesses resulting in malabsorption, such as cystic fibrosis, celiac disease, and inflammatory bowel disease (IBD), all may contribute to nutritional deficiencies that have an influence on bone health. Chronic inflammatory conditions, including IBD and juvenile idiopathic arthritis, may have secondary negative effects on bone health. Secondary conditions associated with bone fragility include endocrine abnormalities, such as hyperthyroidism, hypercortisolism, hyperparathyroidism, growth hormone deficiency, and hypogonadism. Renal disease resulting in chronic kidney disease or renal failure with secondary hyperparathyroidism or idiopathic hypercalciuria, may also impact bone health. Conversely, a history of weight-bearing physical activity appears to be protective against the development of BSI, likely due to deposition of small amounts of new bone on the outer periosteal surface leading to acquired rigidity and increased in strength over time.

Table 15.1
Summary of Medication Effects on Bone.
Adapted with permission Tannirandorn P, Epstein S. Drug-induced bone loss. Osteoporos Int 2000;11(8): 637–659.
Medication Class Specific Medications Mechanism of Effect on Bone Health
Glucocorticoids Prednisone (dose equivalent > 30 g/year)
Budesonide or beclomethasone (high dose, 1500 μg/day for at least 12 months)
Effect on calcium homeostasis:
Decreased intestinal absorption of calcium, increased hypercalciuria, decreased 1,25-(OH) vitamin D receptor activity, increased PTH level and activity.
Effect on sex hormones:
Inhibition of gonadotropins, sex steroids, and adrenal androgen production and release.
Inhibition of bone formation:
Decreased osteoblast function and maturation, promotion of apoptosis of osteoblasts and osteocytes.
Enhanced bone resorption:
Increased osteocyte recruitment, secondary hyperparathyroidism.
Calmodulin-calcineurin phosphatase inhibitors Cyclosporine A
Rapid bone remodeling, increased serum osteocalcin, and loss of cancellous bone.
Medroxyprogesterone acetate (MPA) 3-Month depot medroxyprogesterone acetate injection Suppresses secretion of pituitary gonadotropins and ovarian production of estradiol and estrone. In premenopausal women given progesterones, trabecular bone loss occurs.
Luteinizing hormone-releasing hormone agonists (LHRH-a) Leuprolide acetate
Goserelin acetate
Stimulation of gonadotropins and downregulation of pituitary LHRH receptors. Results in hypogonadism and osteoporosis in men. In women, LHRH-a reduces estrogen production by the ovaries.
Aromatase inhibitors Anastrozole, letrozole, vorozole Inhibition of aromatase, the final enzyme in the biosynthetic pathway converting androgens to estrogens in peripheral tissues.
Anticoagulant Heparin Potentiation of osteoclastic activity, decreased osteoblastic activity, decreased growth factor activity, decreased vitamin D metabolism.
Thyroid hormone replacement therapy Levothyroxine at supraphysiologic doses Increased activation of bone remodeling units, decreased PTH and 1,25-(OH)2 vitamin D synthesis.
Neuroleptics Phenothiazine,
Butyrophenone derivatives (e.g., haloperidol)
Hyperprolactinemic hypogonadism, inhibition of osteoblastic activity.
Methotrexate Inhibition of osteoblastic activity, increased bone resorption.
Antacids Phosphate binders (e.g., aluminum hydroxide) Decreased intestinal phosphate absorption, increased bone resorption, osteomalacia.
Anticonvulsants Phenobarbital, primidone, carbamazepine, diphenylhydantoin Increased active vitamin D metabolites, decreased intestinal calcium transport, secondary hyperparathyroidism, osteomalacia.
Lithium Hyperparathyroidism, osteomalacia.
Sodium fluoride Mineralization defects, impaired bone quality.

Female athletes have a higher incidence of BSI than their male counterparts, even in the setting of sex-comparable sports. In 1992, the Female Athlete Triad was introduced to describe the relationship between energy availability, menstrual function, and BMD. As described in the 2007 position stand on the Triad from the American College of Sports Medicine (ACSM), each component of the Triad may exist on a continuum between optimal health and significant disease. At one end of the spectra, an athlete has adequate energy availability (EA), eumenorrhea, and optimal bone health. Further along the spectra, an athlete may have reduced energy availability, subclinical menstrual disorders (e.g., oligomenorrhea, luteal deficiency, anovulation), and/or low BMD. At the pathologic end of the spectrum an athlete may have low EA with or without disordered eating/eating disorder, functional hypothalamic amenorrhea (FHA, the absence of menses caused by the suppression of the hypothalamic-pituitary-ovarian axis without other known anatomic or organic disease cause), and osteoporosis. Low EA is the underlying cause of the Triad. A female athlete may demonstrate one or more features of the Triad, and research has demonstrated a correlation between greater number of Triad risk factors and increased risk for BSI.

As EA diminishes, physiological changes occur for energy-conserving mechanisms, including lowering resting energy expenditure and diverting energy from the reproductive axis. Studies in adult female athletes have suggested that an EA of at least 30 kcal/kg of fat-free mass (FFM) per day is necessary to maintain proper functioning of the hypothalamic-pituitary-ovarian axis and at least 45 kcal/kg of FFM per day to maintain proper bone metabolism.

In 2014, a more comprehensive term was introduced by the International Olympic Committee (IOC): “relative energy deficiency in sport” (RED-S). RED-S expands on the concept of the Triad to reflect other health and performance consequences resulting from low EA and emphasizes that male athletes are also affected. The underlying etiology of RED-S is low EA, and effects on physiological function include but are not limited to gonadal function, bone health, other endocrine function, metabolism, hematologic function, growth and development, mental health, cardiovascular function, gastrointestinal health, as well as immune function. The potential multisystemic health consequences and performance consequences of RED-S are demonstrated in Figs. 15.1 and 15.2 , respectively. Low EA certainly contributes to impaired bone health in athletes. Low body mass index (BMI) is often used as a surrogate marker for low EA. While BMI is an imperfect marker for EA, low BMI (BMI ≤17.5 kg/m2, <85% predicted weight-for-height in adolescents, and/or >10% weight loss in a 1 month time frame) may suggest low EA and is associated with increased risk of low BMD compared with average-BMI controls in both men and women. This is of particular importance during adolescence, a crucial time for bone accrual, as greater than 90% of peak bone mass is achieved by age 18 years.

Fig. 15.1, Health consequences of relative energy deficiency in sport (RED-S) showing an expanded concept of the Female Athlete Triad to acknowledge a wider range of outcomes and the application to male athletes (∗psychological consequences can either precede RED-S or be the result of RED-S).

Fig. 15.2, Potential Performance consequences of relative energy deficiency in sport (RED-S).

Biomechanical Risk Factors for BSI

Microdamage to bone occurs in the setting of increasing strain magnitude, rate, and total cycles. When cumulative loading of bone exceeds capacity to withstand this mechanical loading, this may result in structural fatigue and deformation. Thus, gait biomechanics contribute to a runner's risk of BSI. Anatomic and static alignment may contribute, including cavus or planus foot type, leg length discrepancy, and greater external rotation range of motion of the hip. Biomechanical patterns correlated with a history of BSI in runners include greater peak hip adduction, knee and tibial internal rotation, knee abduction, and rearfoot eversion in the frontal plane, as well as less knee flexion in the sagittal plane. In studies of running biomechanics in female runners with history of tibial stress injury compared with healthy controls, those with history of BSI were found to have greater average vertical loading and higher peak acceleration. Whereas evidence regarding the significance of the magnitude of ground reaction force (GRF) at initial contact is conflicting, higher GRF loading rate and peak acceleration has been found to be a risk factor for stress fractures and other running-related injuries. Kinematic and kinetic running analyses by Tam et al. demonstrated a positive association between increased ankle dorsiflexion angle at initial ground contact and increased initial loading rate in barefoot runners, with a shift toward greater relative plantar flexion at initial contact predicting a reduction in loading rate.

Other extrinsic factors can modify the load applied to bone. Training factors such as rapid increase in the duration or frequency of running sessions increases the total number of bone loading cycles. Increase in running speed increases GRF. Muscle is typically thought to facilitate the transmission and attenuation of impact forces during the gait cycle. In the setting of muscle fatigue or weakness, the muscle may be less effective in shock attenuation and potentially lead to altered kinematics, subsequently increasing GRF transmitted to the bone and bone strain.

BSI Evaluation

When evaluating a runner with suspected BSI, clinicians should obtain a thorough history and physical exam.

Clinical Presentation and History

In most cases, runners with BSI describe a history that starts with mild diffuse ache that occurs after running. Patients may report pain at a specific point in their running gait cycle when the injured bone is loaded maximally. At the early stages of injury, pain typically resolves soon after the cessation of impact-based activity. As the pathology evolves, the pain becomes more severe and concentrated, requires a shorter duration of running before its onset, and persists for longer periods once running has stopped. Eventually, pain is exacerbated by lower impact activities (e.g., walking), and ultimately a local inflammatory response may manifest as pain while at rest and overlying soft tissue edema and erythema.

Attention should be given to dietary history, history of prior fractures, a detailed running history including running volume and changes in training patterns, shoe type, type of running surface, frequency of races, and any recent changes in running form. Sleep history should be reviewed. Pubertal history and detailed menstrual history should be obtained. Current medications and dietary supplements should be reviewed, along with past history of medication use that may impact bone health, such as hormonal therapies or oral steroids. Family history should include any family history of osteoporosis or pathologic fractures, connective tissue disorders, malabsorptive disorders, endocrine or metabolic disorders, and for female patients, the age of menarche of the patient's mother. If concerned for RED-S in male runners, questions regarding symptoms suggestive of hormonal changes to suggest reduced testosterone (e.g., changes in sexual drive and absence of morning erections) may be included in the review of systems.

Physical Examination

Thorough physical exam should be performed for patients with a clinical suspicion for BSI, both to evaluate for the site of injury and for any underlying conditions that may predispose to BSI. For a more comprehensive discussion of physical exam maneuvers in the evaluation of BSI, please review Chapter 14 , in Clinical Care of the Runner.

Physical exam should also include calculation of BMI and basic vital signs. Individuals with lower BMI, a history of acute food refusal and/or acute weight loss should have orthostatic vital signs recorded. Skin exam should be performed with attention to findings consistent with low EA, such as lanugo-like body hair, dry skin, and even hypercarotenemia. Cardiovascular, respiratory, and abdominal exam may be performed as part of a low EA workup, and thyroid exam and tanner staging may be helpful as part of an endocrine evaluation (e.g., suspected hyperthyroidism, functional hypothalamic amenorrhea). Beighton scoring may be helpful to discern if any global ligamentous laxity is contributing to altered biomechanics and injury risk. Finally, noting other locations of bony tenderness and assessing for blue sclerae in those with a history of prior fractures is important when considering genetic bone diseases, such as osteogenesis imperfecta.

Diagnostic Imaging

Plain radiography is often the first imaging modality considered in the clinical setting for evaluation of stress injury because of its wide availability and relatively low cost. Plain radiographs are often negative soon after injury, with an initial presentation sensitivity of 10%. As BSI symptoms and pathology progress, radiographs become more sensitive (30%–70% sensitivity after 3 weeks of symptoms). BSI may be identified on plain radiography with findings of periosteal thickening or sclerosis, cortical changes with initial decreased density (“gray cortex”), and, later in the disease process, evidence of callus formation or endosteal thickening and sclerosis.

MRI is commonly used in clinical evaluation for BSI because it has high sensitivity and specificity for BSI, does not involve nonionizing radiation, and has value in grading the severity of injury. Multiple grading systems exist for BSI. Two grading systems, the first outlined by Fredericson et al. in 1995 with a more recent update by Nattiv et al. in 2013, are summarized in Table 15.2 . Based on the anatomic location of the injury, BSI can be divided into high-risk and low-risk classifications, reflecting their expected time to heal and risk for nonunion. Table 15.3 demonstrates anatomical locations of high- and low-risk injuries.

Table 15.2
MRI Grading Systems for bone stress injury.
MRI Grade Nattiv et al. 2013 Fredericson et al. 1995
1 Mild marrow or periosteal edema on T2; normal T1 Mild to moderate periosteal edema on T2; normal marrow on T2 and T1
2 Moderate marrow or periosteal edema on T2; normal T1 Moderate to severe periosteal edema on T2; marrow edema on T2 but not T1
3 Severe marrow or periosteal edema on T2 and T1 Moderate to severe periosteal edema on T2; marrow edema on T2 and T1
4 Severe marrow or periosteal edema on T2 and T1; clearly visible fracture line Moderate to severe periosteal edema on T2; marrow edema on T2 and T1; clearly visible fracture line

Table 15.3
High- and Low-Risk bone stress injury by Anatomic Location.
Low Risk High Risk
  • Posteromedial tibia

  • Fibula/lateral malleolus

  • Femoral shaft

  • Diaphysis of second through fourth metatarsals

  • Anterior cortex of tibia

  • Medial malleolus

  • Femoral neck

  • Navicular

  • Sesamoids of the first toe

  • Base of second metatarsal

  • Fifth metatarsal proximal diaphysis

Evaluation of Triad/RED-S in Runners with BSI

In runners diagnosed with BSI, screening for other features of Triad/RED-S is crucial for addressing their individual BSI risk factors and risk for associated health complications. In addition to facilitating healing, the goal is to reduce risk for future injury.

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