# Presentation: 170388

##  Osteoporosis in Spinal Cord Injury

- 		Heidi K. Wennemer, D.O., M.A.Spinal Cord Injury PhysicianVA Boston Health Care SystemWest Roxbury Campus, SCI-128, 1400 VFW Parkway West Roxbury, MA, 02132Office: 857-203-5128Email: Heidi.Wennemer@med.va.govFaculty Harvard and Tufts Medical Schools

## Outline

**Outline**

- Basic Terminology
- Mechanism of Osteoporosis
- Osteoporosis in the General Population
- Special Issues in SCI
- Prevention
- Treatment

## I have no financial, personal, or business interest in any of the medications or treatments mentioned in this lecture.

## Lecture Overview

- The incidence and treatment of osteoporosis varies with age, sex, type, and level of spinal cord injury.
- SCI physicians take care of a wide range of patients               (ASIA A to E).
- Osteoporosis in the general population (applicable to our incomplete patients and aging population)
- Specific issues in para/tetraplegic patients.
- Incidence
- Prevention
- Treatment

## Clinical Definitions

- Osteopenia- reduction in bone mass below the theoretical fracture threshold.
- Osteoporosis- reduction in the bone mass to a level where there is increased risk of fracture in the absence of trauma. Or a fracture has already occurred.

## Slide 6

## Classification:National Osteoporosis Foundation (NOF)	

- Primary
- Type 1- post menopausal
- Type 2- senile
- Secondary
- Medications
- Steroid induced
- Medical conditions
- Spinal cord injury

## Type 1 (postmenopausal)

- Women > Men (6:1 ratio)
- Related to estrogen
- Affects trabecular bone
- Associated with vertebral fractures
- Unrelated to calcium intake
- High bone turnover
- Vertebral compression fractures

## Type 2 (Senile Osteoporosis)

- Elderly Age >75yrs
- Women:Men 2:1
- Calcium deficiency is major factor
- Affects trabecular and cortical bone
- Vertebral compression, hip, and distal radius fxs.
- Slow bone turnover

## Common Locations of Osteoporotic Fractures in General Population

- Thoracic (vertebral) compression fractures
- Hip fractures
- Wrist/extremity fractures.

## Endocrine and metabolicHypogonadismHyperadrenocorticismThyrotoxicosisAnorexia nervosaHyperprolactinemiaPorphyriaHypophosphatasiaType 1 diabetesPregnancyHyperparathyroidismAcromegaly 

Disorders of collagen metabolismOsteogenesis imperfectaHomocystinuriaEhlers-Danlos syndromeMarfan syndrome 

**Endocrine and metabolic**HypogonadismHyperadrenocorticismThyrotoxicosisAnorexia nervosaHyperprolactinemiaPorphyriaHypophosphatasiaType 1 diabetesPregnancyHyperparathyroidismAcromegaly
**Disorders of collagen metabolism**Osteogenesis imperfectaHomocystinuriaEhlers-Danlos syndromeMarfan syndrome

**Nutritional**Malabsorption syndromes, malnutritionChronic liver diseaseGastric operationsVitamin D deficiencyAlcoholism
**Other**Rheumatoid arthritisMyelomaCertain cancersImmobilizationRenal tubular acidosisHypercalciuriaChronic obstructive pulmonary diseaseOrgan transplantationCholestatic liver diseaseMastocytosisThalassemia

## Vitamin D Toxicity
Phenytoin
Glucocorticoids
Phenobarbital
Excessive thyroid hormone replacement 
Heparin
Gonadotropin-releasing hormone antagonists 

- Vitamin D Toxicity
- Phenytoin
- Glucocorticoids
- Phenobarbital
- Excessive thyroid hormone replacement
- Heparin
- Gonadotropin-releasing hormone antagonists

## 
Bone is a living, growing, tissue
Healthy bones are not quiescent. They are constantly being remodeled.
This is not simply a problem of bony destruction, but imbalance between the formation and destruction of bone.
Two types of bone
Cortical
Trabecular

- Bone is a living, growing, tissue
- Healthy bones are not quiescent. They are constantly being remodeled.
- This is not simply a problem of bony destruction, but imbalance between the formation and destruction of bone.
- Two types of bone
- Cortical
- Trabecular

## Bone Physiology. Courtesy Gray's Anatomy  35th edit Longman Edinburgh 1973 

**Bone Physiology. Courtesy Gray's Anatomy  35th edit Longman Edinburgh 1973**

## 80% of the skeletal mass
Provides a protective outer shell around every bone in the body 
Slower turnover
Provides strength and resists bending or torsion

- 80% of the skeletal mass
- Provides a protective outer shell around every bone in the body
- Slower turnover
- Provides strength and resists bending or torsion

## 
20% of the skeletal mass, but 80% of the bone surface. 
less dense, more elastic, and higher turnover rate than cortical bone. 
appears spongy
found in the epipheseal and metaphysal regions of long bones and throughout the interior of short bones. 
constitutes most of the bone tissue of the axial skeleton (skull, ribs and spine).
interior scaffolding maintains bone shape despite compressive forces. 

- 20% of the skeletal mass, but 80% of the bone surface.
- less dense, more elastic, and higher turnover rate than cortical bone.
- appears spongy
- found in the epipheseal and metaphysal regions of long bones and throughout the interior of short bones.
- constitutes most of the bone tissue of the axial skeleton (skull, ribs and spine).
- interior scaffolding maintains bone shape despite compressive forces.

## Types of Cells in Bone Tissue

## OsteoBlasts Build Bone. 

OsteoClasts Create Cavities in bone.

- Osteo_B_lasts _B_uild _B_one.
- Osteo_C_lasts _C_reate _C_avities in bone.

## Bone mass declines with age.

- Remodeling occurs at discrete foci called bone remodeling units (BRUs).
- Number of active BRUs increase with age, resulting in increased bone turn over.
- Osteoblasts are not able to completely fill cavities created by osteoclasts and less mineralized bone is formed.
- Endosteal bone loss is partially compensated by periosteal bone formation. This leads to trabecular thinning.

## Bone Remodeling Unit

**Bone Remodeling Unit**

- Osteoclast
- Osteoblast
- New bone
- Lining cells

## Bone turnover

- In cortical bone, osteoclasts create resorption tunnels parallel to the long axis of the bone and the osteoblasts fill in the tunnel with new bone.
- In trabecular bone, osteoclasts create shallow excavations toward the center, which the osteoblasts then fill in with new bone.
- Bone formation by the osteoblast always follows osteoclastic resorption at the same resorption site.

## In trabecular bone it takes 3-6 months to complete a remodeling cycle, with about 1 month for resorption followed by 5 months for formation Baron et al 1999. 
It is estimated that the remodeling cycle takes longer in cortical bone Einhorn, 1996. 

- In trabecular bone it takes 3-6 months to complete a remodeling cycle, with about 1 month for resorption followed by 5 months for formation Baron et al 1999.
- It is estimated that the remodeling cycle takes longer in cortical bone Einhorn, 1996.

## Microscopic Anatomy of Osteoporotic Bone

- Osteoporotic bone has a normal ratio of osteoid to mineral.
- Osteoid is the uncalcified bone matrix, produced by osteoblasts, and made up of type I collagen and ground substance.
- Trabecular (Cancellous) bone is composed of vertical and horizontal trabecular struts.
- This interconnectivity between struts gives trabecular bone its greatest compressive strength.
- Predisposition to loose horizontal struts.
- Leads to unsupported vertical struts that are susceptible to fracture with axial loading.

-  www.grad.ucl.ac.uk

## Slide 25

## A Common Problem in the General Population	

- 100 million people at risk worldwide
- 28 million people at risk in US
- 18 million people with osteopenia
- Loss of 1 S.D. has 2.5 times the risk of hip fracture and a two fold increase in risk of spine fracture.

## Slide 27

## Mortality

- Survival rates after vertebral, hip, and distal forearm fracture
- 60% survival 5 years after vertebral fracture and 50% survival 5 years after hip fracture. Mortality due to any cause.

## Testing: Bone Mineral Density	

- Duel-energy X-ray absoptiometry (DEXA)
- *Most precise and cost efficient
- Quantitative Ultrasonography of the Heel
- No radiation. Poor precision. Poor correlation with DEXA. Generally not recommended.
- Quantitative Computed Tomorgraphy (QTC)
- Generally used for research. Lower precision and higher radiation. Better at measuring trabecular bone.

## DEXA

- Typically measured at L1-L4, and at the proximal femur (hip)
- X-rays at two energy levels used
- Bone mineral content (BMC) is calculated using the difference in absorption of x-rays between bone and soft tissue.
- Bone mineral density (BMD) = BMC/ area
- BMD is then compared to reference data and expressed as T and Z scores.

## Represents distribution of biological variables including bone density. 
66% of normal values will fall between -1 and +1 SD 
34% outside with 17% above and  17% below). 

http://www.rah.sa.gov.au/nucmed/BMD/bmd_docguide.htm

- Represents distribution of biological variables including bone density.
- 66% of normal values will fall between -1 and +1 SD
- 34% outside with 17% above and  17% below).
- http://www.rah.sa.gov.au/nucmed/BMD/bmd_docguide.htm

## Severe osteoporosis (or established osteoporosis)	BMD > 2.5 Standard Deviations (SD) below the 	young adult mean value with one or more 	fragility fractures.
Osteoporosis	BMD > 2.5 Standard Deviations (SD) below the 	young adult mean value.
Low bone mass (or osteopenia)	BMD between 1 and 2.5 Standard Deviations 	(SD) below the young adult mean value. 
Normal	BMD < 1 Standard Deviation (SD) below the 	young adult mean value.

**Severe osteoporosis (or established osteoporosis)**	BMD > 2.5 Standard Deviations (SD) below the 	young adult mean value _with_ one or more 	fragility _fractures_.
**Osteoporosis**	BMD > 2.5 Standard Deviations (SD) below the 	young adult mean value.
**Low bone mass (or osteopenia)**	BMD between 1 and 2.5 Standard Deviations 	(SD) below the young adult mean value.
**Normal**	BMD < 1 Standard Deviation (SD) below the 	young adult mean value.

## DEXA

- T score (same as standard deviation)
- Compares patient’s BMD with mean value in young adult white women.
- Male databases and other ethnic databases are emerging.
- Z score (standard deviation from an age and sex adjusted median)
- Patient’s BMD compared to mean value in a population of similar age, sex, and height.

## Slide 35

## MRI can detect thoracic compression fractures with high sensitivity.
Acute fractures have increased signal due to edema.
MRI can detect soft tissue abnormalities (edema, hemorrhage, infection, ischemia).
Can differentiate osteoporotic fractures from pathologic fractures.

- MRI can detect thoracic compression fractures with high sensitivity.
- Acute fractures have increased signal due to edema.
- MRI can detect soft tissue abnormalities (edema, hemorrhage, infection, ischemia).
- Can differentiate osteoporotic fractures from pathologic fractures.

## Compression Fracture

- T2

- T1

## DEXA Screening Recommendations

- National Osteoporosis Foundations (NOF) recommends bone densitometry in
- All post menopausal white women under 65 years of age with at least one risk factor.
- All white women after age 65 regardless of risk factors.
- Recommendations for men and other populations including SCI are not as clear.

## Other Indications for BMD Testing

- Estrogen deficiency
- Prolonged glucocorticoid therapy
- Fracture
- Osteopenia
- Primary hyperparathyroidism
- Monitoring of medical therapy for osteoporosis
- Typically every 1-2 years.
- Spinal cord injury*

## Risk Factors for Osteoporotic FracturesFrom the National Osteoporosis Foundation (NOF)

- Non modifiable
- Caucasian or Asian
- Advanced age
- Female
- Dementia
- Poor Health
- Fracture in 1st degree relative
- Personal history of fracture * 5 fold increase

## Significantly increased risk of second fracture during the ONE year observation period.
Authors estimated a 5 fold risk of second fracture with personal history of one or more fractures.

Risk of New Vertebral Fracture in the Year Following a Fracture, Lindsay et al.JAMA. 2001;285:320-323. 

- Significantly increased risk of second fracture during the ONE year observation period.
- Authors estimated a 5 fold risk of second fracture with personal history of one or more fractures.
- Risk of New Vertebral Fracture in the Year Following a Fracture, Lindsay et al.JAMA. 2001;285:320-323.

## Risk Factors for Osteoporotic FracturesFrom the National Osteoporosis Foundation (NOF)

- Potentially modifiable
- Low body weight <127lb
- Estrogen deficiency
- Early menopause <45 or bilateral oopherectomy
- Prolonged amenorrhea >1yr
- Impaired vision
- Alcoholism
- Cigarette smoking
- Recurrent falls
- Inadequate physical activity
- Low calcium intake

## Osteoporosis in Men

- 2 million men have osteoporosis and millions more have low BMD.
- 1 in 8 men over 50 will have an osteoporosis induced fracture in their lifetime.
- Work up for a new diagnosis of osteoporosis in males 					includes laboratory testing.

## anticonvulsant medications 
thyrotoxicosis 
hyperparathyroidism 
immobilization 
osteogenesis imperfecta 
homocystinuria 
neoplastic disease 
ankylosing spondylitis and rheumatoid arthritis 
systemic mastocytosis 

- anticonvulsant medications
- thyrotoxicosis
- hyperparathyroidism
- immobilization
- osteogenesis imperfecta
- homocystinuria
- neoplastic disease
- ankylosing spondylitis and rheumatoid arthritis
- systemic mastocytosis

- glucocorticoid medications
- immunosuppressive drugs
- hypogonadism (low testosterone levels)
- excessive alcohol consumption
- smoking
- chronic obstructive pulmonary disease and asthma
- cystic fibrosis
- gastrointestinal disease
- hypercalciuria

## Serum calcium
Urine calcium
Phosphate 
Alkaline phosphatase 
Thyroid function 
Testosterone 
Urinary N-telopeptide
Homocystine increased homocysteine level appears to be a strong 	independent risk factor for osteoporotic fractures in older men and women. VanMeurs et al NEJM 2004.
 Cortisol
PTH

- Serum calcium
- Urine calcium
- Phosphate
- Alkaline phosphatase
- Thyroid function
- Testosterone
- Urinary N-telopeptide
- Homocystine increased homocysteine level appears to be a strong 	independent risk factor for osteoporotic fractures in older men and women. VanMeurs et al NEJM 2004.
-  Cortisol
- PTH

## Osteoporosis in Spinal Cord Injury (SCI)

## Osteoporosis in SCI

- “An inevitable complication of spinal cord injury (SCI) is osteoporosis, characterized by decreased bone mass, deterioration of bone tissue, and increased susceptibility to fracture”.
- Oleson, UAB Insight, Online publication, Spring 2005.

## Osteoporotic Bone in SCI

**Osteoporotic Bone in SCI**

## 
“The body that has sustained SCI has been considered the model of premature aging”. 

www.emedicine.com/pmr/byname/ osteoporosis-and-spinal-cord-injury.htm 

- “The body that has sustained SCI has been considered the model of premature aging”.
- www.emedicine.com/pmr/byname/ osteoporosis-and-spinal-cord-injury.htm

## Osteoporosis in SCI: Mechanism

- Bone turnover significantly increased after SCI.
- Osteoclastic activity increases without significant change in osteoblastic production. Chen & Stein, Top SCI Rehab, 2003.
- Results in bone hyperresorption and osteoporosis.
- This model at the skeletal level following SCI resembles the high bone turnover rate seen in postmenopausal osteoporosis (Type 1).

## The activity of both osteoblasts and osteoclasts is triggered by the SCI.
Markers of osteoblastic activity rise only slightly, while osteoclasts have a significant increase in their activity.
Osteoclast activity peaks at 10 weeks following the SCI with values 10 times the upper limits of normal. 

- The activity of both osteoblasts and osteoclasts is triggered by the SCI.
- Markers of osteoblastic activity rise only slightly, while osteoclasts have a significant increase in their activity.
- Osteoclast activity peaks at 10 weeks following the SCI with values 10 times the upper limits of normal.

## This hyperresorption is not only due to immobilization. 
The mechanisms of bone loss in SCI and bone hyperresorption may be different in acute and chronic SCI. 
In acute SCI, immobilization is an important factor.
As in able bodied persons, immobilization results in hypercalcemia, hypercalciuria, and trabecular bone loss. 
The urinary calcium level in SCI is 2-4 times higher than able bodied subjects on prolonged bed rest. Maynard, APMR 1986.
The loss of bone also may be enhanced by lack of muscle traction on bone or other neural factors associated with SCI. 

- This hyperresorption is not only due to immobilization.
- The mechanisms of bone loss in SCI and bone hyperresorption may be different in acute and chronic SCI.
- In acute SCI, immobilization is an important factor.
- As in able bodied persons, immobilization results in hypercalcemia, hypercalciuria, and trabecular bone loss.
- The urinary calcium level in SCI is 2-4 times higher than able bodied subjects on prolonged bed rest. Maynard, APMR 1986.
- The loss of bone also may be enhanced by lack of muscle traction on bone or other neural factors associated with SCI.

## Markers for bone formation such as Alk Phos and osteocalcin are normal after SCI unless pt develops heterotopic ossification (H.O.).
PTH is suppressed when ionized calcium increases at 2-3 wks post SCI and remains suppressed for at least 24 wks.

- Markers for bone formation such as Alk Phos and osteocalcin are normal after SCI unless pt develops heterotopic ossification (H.O.).
- PTH is suppressed when ionized calcium increases at 2-3 wks post SCI and remains suppressed for at least 24 wks.

## Vitamin D deficiency may also contribute to bone loss in SCI.
1,25 D (active form of Vit D) is significantly lower in SCI pts.
PTH is also suppressed. 
Suspect secondary vitamin D deficiency due to PTH suppression in acute SCI.

- Vitamin D deficiency may also contribute to bone loss in SCI.
- 1,25 D (active form of Vit D) is significantly lower in SCI pts.
- PTH is also suppressed.
- Suspect secondary vitamin D deficiency due to PTH suppression in acute SCI.

## The parathyroid glands secrete parathyroid hormone (PTH) when serum calcium levels are too low
 PTH stimulates the activity of the 1-hydroxylase enzyme in the kidney, resulting in increased production of calcitriol, the biologically active form of vitamin D3.
Increased calcitriol production increases serum calcium levels by:
activating the vitamin D-dependent transport system in the small intestine to  increase absorption of dietary calcium
increasing the reabsorption of calcium by the kidneys. 
 increasing the mobilization of calcium from bone into the circulation *stimulating bone reabsorption. 

-  PTH stimulates the activity of the 1-hydroxylase enzyme in the kidney, resulting in increased production of calcitriol, the biologically active form of vitamin D3.
- Increased calcitriol production increases serum calcium levels by:
- activating the vitamin D-dependent transport system in the small intestine to  increase absorption of dietary calcium
- increasing the reabsorption of calcium by the kidneys.
-  increasing the mobilization of calcium from bone into the circulation *stimulating bone reabsorption.

## Pts with acute SCI had significant 
Suppression of PTH
Suppression of 1,25 vit D
Elevation of phosphorus
Elevation of prolactin
PTH suppression was associated with degree of neurologic impairment complete SCI > incomplete SCI > brain injury.

- Pts with acute SCI had significant
- Suppression of PTH
- Suppression of 1,25 vit D
- Elevation of phosphorus
- Elevation of prolactin
- PTH suppression was associated with degree of neurologic impairment complete SCI > incomplete SCI > brain injury.

## Acutely, the parathyroid gland is relatively inactive with low parathyroid hormone levels observed up until the 1-year point following injury. 
Hypercalcemia seen immediately post injury is believed to lead to this low PTH level. 
Parathyroid activity increases from years 1-9 and may even become hyperactive. 

- Acutely, the parathyroid gland is relatively inactive with low parathyroid hormone levels observed up until the 1-year point following injury.
- Hypercalcemia seen immediately post injury is believed to lead to this low PTH level.
- Parathyroid activity increases from years 1-9 and may even become hyperactive.

## Proposed Mechanism in SCI: calcium

- Chronic SCI patients may develop low serum calcium levels.
- Absorption of calcium from the gastrointestinal tract has also been found to decrease in the acute period following SCI.
- Until recently, dietary calcium _reduction_ was commonly recommended as a way to decrease calcium excretion and prevent the complications of hypercalciuria.
- Dietary calcium restriction is no longer recommended.

## Elevated serum ionized calcium noted from 2 to 24 wks post injury.
Urine calcium is even more dramatically increased than serum calcium in SCI patients.
Hypercalciuria was observed in almost all SCI patients in the acute phase..
Urine calcium excretion normalized over 9 months (post SCI) and dropped to lower than normal levels within 3 years. 
Urine and serum calcium levels are not specific for bone resorption and can be affected by diet.

- Elevated serum ionized calcium noted from 2 to 24 wks post injury.
- Urine calcium is even more dramatically increased than serum calcium in SCI patients.
- Hypercalciuria was observed in almost all SCI patients in the acute phase..
- Urine calcium excretion normalized over 9 months (post SCI) and dropped to lower than normal levels within 3 years.
- Urine and serum calcium levels are not specific for bone resorption and can be affected by diet.

## Cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and insulin like growth factor (IGF-1) help regulate bone resorption and bone formation.
IL-1 and TNF- α stimulate bone resorption
IGF-1 induces bone formation.
In SCI patients IL-1 and TNF-α were found to be elevated 
IGF-1 production and response to IGF-1 was diminished. 
This combination of increased IL-1/TNF-α with decreased IGF-1 could partially explain the bone hyperresorption seen in SCI

- Cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and insulin like growth factor (IGF-1) help regulate bone resorption and bone formation.
- IL-1 and TNF- α stimulate bone resorption
- IGF-1 induces bone formation.
- In SCI patients IL-1 and TNF-α were found to be elevated
- IGF-1 production and response to IGF-1 was diminished.
- This combination of increased IL-1/TNF-α with decreased IGF-1 could partially explain the bone hyperresorption seen in SCI

## NTx N-telopeptide is the N-terminal intermolecular cross-linking domain of type I collagen
NTx is a sensitive and specific marker for bone resorption
Ntx is significantly increased in urine of pts after SCI, confirming bone hyperresorption
Increased urine NTx can be observed as early as 9 days post SCI and may peak 10-16 wks post SCI.
Increased NTx can last several years after SCI.

Adapted from Chen & Stein, Top SCI Rehab, 2003.

- NTx N-telopeptide is the N-terminal intermolecular cross-linking domain of type I collagen
- NTx is a sensitive and specific marker for bone resorption
- Ntx is significantly increased in urine of pts after SCI, confirming bone hyperresorption
- Increased urine NTx can be observed as early as 9 days post SCI and may peak 10-16 wks post SCI.
- Increased NTx can last several years after SCI.
- Adapted from Chen & Stein, Top SCI Rehab, 2003.

## Proposed Mechanism of Bone Hyperresorption in SCI: adapted from Chen & Stein, Top SCI Rehab, 2003.

** ****Acute Spinal Cord Injury**

**Immobilization**
**Neurovascular Changes**
**Decreased IGF-1 production**
**Increased resistance to IGF-1**
**Increased cytokines (IL-1, TNF-****α****)**

**Increased Osteoclast Activity**

**Bone Hyperresorption**

## Bone Hyperresorption

**Bone Hyperresorption**

**Nephrocalcinosis**
**Ectopic calcification**

** ****Nephrolithiasis****	**

**       ****Fracture**

**Hypercalcemia****	**

** ****Hypercalciuria****	**

**  ****Osteoporosis**

**Inhibited PTH**

**Decreased 1,25 D**

**Increased markers:**
**NTx**
**Hydroxyproline**
**Deoxypyridnolin**

## After SCI serum calcium and ionized calcium are typically elevated, but may remain in high normal range. 
Incidence of true hypercalcemia in SCI not clear, studies report 2.6-23%.
Highest risk of hypercalcemia is in adolescent and young adult males
Increased serum calcium can occur from a few days to several weeks post SCI. 

Adapted from Chen & Stein, Top SCI Rehab, 2003.

- After SCI serum calcium and ionized calcium are typically elevated, but may remain in high normal range.
- Incidence of true hypercalcemia in SCI not clear, studies report 2.6-23%.
- Highest risk of hypercalcemia is in adolescent and young adult males
- Increased serum calcium can occur from a few days to several weeks post SCI.
- Adapted from Chen & Stein, Top SCI Rehab, 2003.

## Hypercalcemia:Bone and Calcium Metabolism in SCI

- Hypercalcemia, higher incidence in
- Children and adolescent
- Acute SCI
- Males
- Complete SCI
- High cervical injury
- Dehydration
- Prolonged immobilization

## Symptoms of Hypercalcemia

- Nausea
- Vomiting
- Anorexia
- Fatigue
-  lethargy
- Polydipsia
- Polyuria
- Dehydration

## Treatment of Hypercalcemia in SCI

- Treat if symptomatic or serum calcium is >12mg/dl.
- IV Normal saline to enhance urinary excretion of calcium
- Foley insertion
- IV Pamidronate or other bisphosphonate

## Prevalence of Osteoporosis in Male SCI Patients Lazo et al, 2001

- Osteoporosis ~ 60%
- Osteopenia ~ 20%
- Fractures ~ 34%
- Prevalence is even higher in female SCI patients.
- Photo: Eugene Roberts, the first unofficial wheelchair athlete crossing the finish line with his brother, Jim, on April 20, 1970. Boston Globe

## Morbidity and Mortality in SCI due to Osteoporosis:

- The most measurable complication of osteoporosis following SCI is pathologic fracture.
- Incidence of  Pathologic Fracture in SCI based on time since injury
**14% of pts had at least one fracture at 5 years, **
**28% at 10 years, and **
**39% at 15 years post injury.**
- Model Spinal Cord Injury System incidence rates (based on outpatient studies)

## Studies suggest SCI patients lose a third of their bone mineral density (BMD) in the first year following SCI.
Decline in bone mineral density has been detected with DEXA in SCI pts as early as 6 wks after SCI. 
Bone loss progresses of next 12-16 months after SCI. 
Bone loss after SCI reaches “fracture threshold” 1-5 years after injury. 

Lazo et al, Spinal Cord, 2001 

- Studies suggest SCI patients lose a third of their bone mineral density (BMD) in the first year following SCI.
- Decline in bone mineral density has been detected with DEXA in SCI pts as early as 6 wks after SCI.
- Bone loss progresses of next 12-16 months after SCI.
- Bone loss after SCI reaches “fracture threshold” 1-5 years after injury.
- Lazo et al, Spinal Cord, 2001

## Almost 1/3 of bone mass is lost within 3-4 months post SCI. 
In the first few months after SCI, the DEXA scan can not detect bone loss.  
After 6-18 months, osteoporosis below the level of injury is almost always present and can be detected on DEXA scan. 

Chen & Stein, Top SCI Rehab, 2003.

- Almost 1/3 of bone mass is lost within 3-4 months post SCI.
- In the first few months after SCI, the DEXA scan can not detect bone loss.
- After 6-18 months, osteoporosis below the level of injury is almost always present and can be detected on DEXA scan.
- Chen & Stein, Top SCI Rehab, 2003.

## Some Bones Loose More Than Others After Spinal Cord Injury (SCI)

- Bone loss following SCI occurs throughout the skeletal system, with the exception of the skull.
- Areas rich in trabecular bone are demineralized to the greatest degree.
- The distal femur and proximal tibia are most affected, followed by the pelvis and the arms.
- Demineralization in the skull, pelvis, and lower limbs is independent of neurologic level.

## This chronic-stage mechanism of osteoporosis 
increase in bone mineral in regions of the body in which weight bearing is resumed (eg, in the upper extremities, spine) 
further demineralization observed in regions that are chronically non–weight-bearing (eg, the pelvis, lower extremities). 

- This chronic-stage mechanism of osteoporosis
- increase in bone mineral in regions of the body in which weight bearing is resumed (eg, in the upper extremities, spine)
- further demineralization observed in regions that are chronically non–weight-bearing (eg, the pelvis, lower extremities).

## Over 50% of bone content in arms and trunk is demineralized after 10 yrs. 
The arms and trunk begin to have an increase in BMC after 4 months. 
The net effect is an approximate 10-21% loss of total bone at the 10-year point.
Interestingly, the trunk has a net gain in mineral content by 12 years post-injury. 

- Over 50% of bone content in arms and trunk is demineralized after 10 yrs.
- The arms and trunk begin to have an increase in BMC after 4 months.
- The net effect is an approximate 10-21% loss of total bone at the 10-year point.
- Interestingly, the trunk has a net gain in mineral content by 12 years post-injury.

## Bone density is known to correlate inversely with fracture risk.
Precise measurement of bone density allows us to quantify fracture risk before fracture occurs.
Should we be measuring bone density in all SCI patients?

- Bone density is known to correlate inversely with fracture risk.
- Precise measurement of bone density allows us to quantify fracture risk before fracture occurs.
- Should we be measuring bone density in all SCI patients?

## High Risk of Fracture in SCI

- When compared to the general population, the risk of hip/femoral fracture in spinal cord injured patients is:
-  104 times more likely at age 50
-  24 times more likely at age 70
- Frisbie, JSCM, 20: 1, 1997.

## Fracture Incidence in SCI vs. General Population

- Frisbie, JH. Fractures After Myelopathy: The Risk Quantified. J Spinal Cord Med 1997; 20:66-69

- 0

- 10

- 20

- 30

- 40

**Femur Fracture  Events/ **1000 patient years

- 30		40	50	60	70	80

- 104X

- 24X

**Age (years)**

- SCI

**General **
**Population**

## Osteoporotic bone

- Osteoporotic fracture

## Slide 79

## Overview of Fractures in SCI

- The sites of fractures mimic the sites of greatest osteoporosis, with the supracondylar region and tibia being the most common.
- A bone mineral density fracture threshold of 50% appears to exist for the knee, and this most likely is the bone mineral density fracture threshold for most regions in the body.
- Fracture rates in the lower extremities are 10 times greater in patients with complete SCI compared to patients with incomplete injuries.

## Paraplegic patients are at higher risk than tetraplegic patients, due to the higher level of function that paraplegic individuals have with increased mobility and participation in physical activities. 
The inciting events that lead to fractures frequently are unknown or associated with relatively minimal traumas. 
Less torque is needed to produce failures in bone in the SCI population than in individuals who have not sustained SCI. 
Can occur with minimal trauma
Deformity may be only sign in complete spinal cord injury.

- Paraplegic patients are at higher risk than tetraplegic patients, due to the higher level of function that paraplegic individuals have with increased mobility and participation in physical activities.
- The inciting events that lead to fractures frequently are unknown or associated with relatively minimal traumas.
- Less torque is needed to produce failures in bone in the SCI population than in individuals who have not sustained SCI.
- Can occur with minimal trauma
- Deformity may be only sign in complete spinal cord injury.

## Sex:	 Women are more likely to develop osteoporosis after SCI than men.
Age: For every 1-year increase in age, the rate of developing osteoporosis of the knees was shown to increase by 3.54%.
Level of Injury
Severity of Injury
Don’t forget about all of the modifiable and non-modifiable risk factors the apply to general population.

- Sex:	 Women are more likely to develop osteoporosis after SCI than men.
- Age: For every 1-year increase in age, the rate of developing osteoporosis of the knees was shown to increase by 3.54%.
- Level of Injury
- Severity of Injury
- Don’t forget about all of the modifiable and non-modifiable risk factors the apply to general population.

## Level of Injury: Para vs Tetraplegia

- Significant differences in upper extremity bone density are observed between paraplegic patients and tetraplegic patients.
- The bone mineral density of the arms of paraplegic patients returns to near normal by the 10-year post injury point, which is approximately 16% more bone mineral than is found in the arms of tetraplegic patients.

## graph

## Para vs Tetraplegia Garland et al 1992.

- DEXA in males aged less than 40 years after complete traumatic paraplegic and quadriplegic spinal cord injury.
- Paraplegic and quadriplegic subjects were significantly different only at the arms and trunk, but were highly similar at the pelvis and below.
- As expected osteoporosis is below the level of injury.

## Individuals with complete injuries have lower bone mineral density than those with incomplete lesions. 
lower lumbar spine bone mineral densities (z value -1.47) 1-26 years post injury. 
Individuals with incomplete motor SCI demonstrate greater bone mineral density at the areas of greater lower extremity muscle strength. 

- Individuals with complete injuries have lower bone mineral density than those with incomplete lesions.
- lower lumbar spine bone mineral densities (z value -1.47) 1-26 years post injury.
- Individuals with incomplete motor SCI demonstrate greater bone mineral density at the areas of greater lower extremity muscle strength.

## Greater suppression of PTH/vitamin D axis in complete than incomplete injury. Mechanick et al, APMR 1997
Degree of bone hyperresorption and PTH suppression is not associated with level of injury. 
Incidence of pathologic fractures in the lower extremity are much higher in complete (7%) than incomplete (0.7%) spinal cord injuries.

- Greater suppression of PTH/vitamin D axis in complete than incomplete injury. Mechanick et al, APMR 1997
- Degree of bone hyperresorption and PTH suppression is not associated with level of injury.
- Incidence of pathologic fractures in the lower extremity are much higher in complete (7%) than incomplete (0.7%) spinal cord injuries.

## A positive correlation exists between the time following the injury and degree of bone loss. 
Rapid loss of bone mineral occurs during the first 4 months following SCI. 
In patients with injury less than 1 year, there was a up to a 43% reduction in bone mineral densities when compared with controls: femoral neck (27%), midshaft (25%), and distal femur (43%). 
After the first year, bone mineral loss continues at a slower rate in the pelvis and lower extremities.

- A positive correlation exists between the time following the injury and degree of bone loss.
- Rapid loss of bone mineral occurs during the first 4 months following SCI.
- In patients with injury less than 1 year, there was a up to a 43% reduction in bone mineral densities when compared with controls: femoral neck (27%), midshaft (25%), and distal femur (43%).
- After the first year, bone mineral loss continues at a slower rate in the pelvis and lower extremities.

## Some controversy exists surrounding the protective effect of spasticity on bone mineral content. 
Recent studies demonstrate a higher bone density in patients with spasticity when compared to those with flaccid paralysis. 

- Some controversy exists surrounding the protective effect of spasticity on bone mineral content.
- Recent studies demonstrate a higher bone density in patients with spasticity when compared to those with flaccid paralysis.

## Lab Studies in SCI

- serum calcium
- phosphorous
- alkaline phosphatase
- 1,25–dihydroxyvitamin D
- calcitonin
- urinary calcium
- Hydroxyproline
- N-telopeptide

## Physical Therapy in SCI

- The effect of remobilization on SCI-induced osteoporosis has been well studied.
- Weight-bearing exercises with standing frames and bikes, or using functional electrical stimulation (FES) have been shown to be effective when started within 6 weeks of injury.
- These same programs can be used in the chronic SCI population, but were shown to be ineffective in preventing osteoporosis or restoring bone mineral.

## Prevention in SCI

- In the acute and chronic stages of SCI
- Appropriate nutritional intake of calcium and vitamin D.
- Proper precautions in transfers and wheelchair sports.
- Patient education to prevent osteoporosis and fractures.
- Appropriate amounts of calcium intake and early mobilization have important means of limiting mineral loss.

## General Prevention Applicable to SCI 

- Adequate calcium intake (1500 mg/day)
- Vit D intake 600-1000 IU/day
- Weight bearing exercise (FES, Standing frame, Bike, Locomat)
- Minimize alcohol intake
- Quit smoking
- Medication

## Cyclic etidronate is shown to prevent BMD loss in acute SCI when given 800mg qd for 2 wks. Pearson et al, APMR, 1997.
Pamidronate (iv) 30mg iv x 3 days given with vitamin D and calicum inhibits bone resorption and reverses inhibition of PTH. Chen and Stein, JSCM, 2001.
30mg pamidronate monthly for 6 months with calcium inhibits bone hyperresorption and significantly reduces bone loss. Nance et al, APMR, 1999.
Aledronate and tiludronate have also been found to be effective.
Several different bisphosphonates have been shown to be effective. No one drug is clearly better than the others.
The long term effects and risks of treatment with bisphosphonates is unknown.

- Cyclic etidronate is shown to prevent BMD loss in acute SCI when given 800mg qd for 2 wks. Pearson et al, APMR, 1997.
- Pamidronate (iv) 30mg iv x 3 days given with vitamin D and calicum inhibits bone resorption and reverses inhibition of PTH. Chen and Stein, JSCM, 2001.
- 30mg pamidronate monthly for 6 months with calcium inhibits bone hyperresorption and significantly reduces bone loss. Nance et al, APMR, 1999.
- Aledronate and tiludronate have also been found to be effective.
- Several different bisphosphonates have been shown to be effective. No one drug is clearly better than the others.
- The _long term_ effects and risks of treatment with bisphosphonates is unknown.

## Mechanism of Action Bisphosphonates		

- Inhibit osteoclast mediated bone resorption
- Inhibit osteoclast
- Activity
- Recruitment
- Adhesion
- Osteoclast apoptosis

## N2 (nitrogen)

- Ca (calcium)

## Use urinary N-telopeptide (NTx) as “an indicator for the need for treatment” in acute SCI.
If N-telopeptide is elevated
Start vitamin D and calcium. Must pretreat with at least 3 days of calcium and D, then continue these after tx.
Give a single dose of iv pamidronate (90mg). One dose can bring N-telopeptide into the normal range.
Pamidronate can cause hypocalcemia, so calcium levels should be monitored 3-5 days after tx. 
After discharge weekly alendronate (70mg) or risedronate (30mg), and daily Vit D and calcium.
Check NTx at 1 month, 3 months, 6 months, and annually after tx.
? Benefit of quarterly testing of urine N-telopeptide.

- Use urinary N-telopeptide (NTx) as “an indicator for the need for treatment” in acute SCI.
- If N-telopeptide is elevated
- Start vitamin D and calcium. Must pretreat with at least 3 days of calcium and D, then continue these after tx.
- Give a single dose of iv pamidronate (90mg). One dose can bring N-telopeptide into the normal range.
- Pamidronate can cause hypocalcemia, so calcium levels should be monitored 3-5 days after tx.
- After discharge weekly alendronate (70mg) or risedronate (30mg), and daily Vit D and calcium.
- Check NTx at 1 month, 3 months, 6 months, and annually after tx.
- ? Benefit of quarterly testing of urine N-telopeptide.

## 
Must Monitor Response to bisphosphonate therapy
Repeat DEXA in 1-2 yrs
Follow bone serum/urine markers at 1 month, 3 months, 6 months, and annually (NTX). 
Consider stopping medication after 2-5 years.
If yearly NTX levels become elevated, resume medication.
In non SCI pts, bone loss resumes within 1year of discontinuation of bisphosphonate but if pt was tx 2-5 years, the suppression of bone resorption may last for 2 years.
Lifelong tx ? Risk vs benefit.

- Must Monitor Response to bisphosphonate therapy
- Repeat DEXA in 1-2 yrs
- Follow bone serum/urine markers at 1 month, 3 months, 6 months, and annually (NTX).
- Consider stopping medication after 2-5 years.
- If yearly NTX levels become elevated, resume medication.
- In non SCI pts, bone loss resumes within 1year of discontinuation of bisphosphonate but if pt was tx 2-5 years, the suppression of bone resorption may last for 2 years.
- Lifelong tx ? Risk vs benefit.

## Summary

- Prevalence of Osteoporosis and Fractures due to Osteoporosis in SCI is very high.
- Fractures cause significant morbidity and mortality.
- Bone loss occurs quickly after SCI.
- Bone loss is rapid for first 18 months, but continues throughout the pts life.
- Overall incidence in SCI.
- Osteoporosis (~60%)
- Osteopenia (~20%)
- Fractures (~34%)
- Lazo et al, 2001.

## Recommendations	 for Acute SCI

- Think About Bone Hyperresorption and Osteoporosis
- Check N telopeptide level in acute SCI.
- Treat patients with elevated NTX before there is extensive bone loss or fracture occurs.
- Current no treatment regimen will significantly increase bone density.
- Key is Prevention and Education

## Bone mineral density (BMD) should be measured in all SCI patients at baseline, and again after 1 year with DEXA scan.
Any SCI patient with one or more risk factors in addition to SCI must have a baseline BMD (smoking, age over 65). 
High risk patients (previous fracture or more than one risk factor in addition to SCI) should have DEXA done serially (every 1-2yrs) to follow BMD.
Patients on treatment for osteoporosis should have response to therapy monitored with  
serial DEXA (every 1-2 years) 
Annual urine NTX level

- Bone mineral density (BMD) should be measured in all SCI patients at baseline, and again after 1 year with DEXA scan.
- Any SCI patient with one or more risk factors in addition to SCI must have a baseline BMD (smoking, age over 65).
- High risk patients (previous fracture or more than one risk factor in addition to SCI) should have DEXA done serially (every 1-2yrs) to follow BMD.
- Patients on treatment for osteoporosis should have response to therapy monitored with
- serial DEXA (every 1-2 years)
- Annual urine NTX level

## Encourage appropriate weight bearing exercise such as weight lifting, or standing frame.
Do not be afraid of calcium supplements or calcium in diet (Stuart et al NEJM 1982).
Ask about modifiable risk factors and educate pts.

- Encourage appropriate weight bearing exercise such as weight lifting, or standing frame.
- Do not be afraid of calcium supplements or calcium in diet (Stuart et al NEJM 1982).
- Ask about modifiable risk factors and educate pts.