Osteoporosis

Osteoporosis is a chronic, progressive metabolic bone disease of multifactorial etiology. It is characterized by low bone density and deterioration of the microarchitecture of bone tissue, placing affected patients at risk of fragility fractures. Fragility fractures carry a high morbidity and disease burden, especially with fractures of the hip and vertebrae.

Moreover, osteoporosis currently is surprisingly poorly managed by clinicians - fewer than 20% of women and 10% of men receive therapies to prevent further fractures after suffering a fragility fracture (as compared to CVD where 75% of patients receive B-blockers post MI). Until recently, there did not exist a clear consensus on how to screen for osteoporosis, and there still exists a disconnect where a high portion (44-82%) of women with fragility fractures are NOT assessed or treated for osteoporosis.

Pathophysiology
Bone remodeling involves osteoclasts in breaking down bone matrix, over a period of weeks, and osteoblasts in rebuilding and remodeling new bone, a process that occurs over months.

Over time, bone remodeling results in net bone loss, especially in the presence of factors (eg. estrogen deficiency) that increase the rate of remodeling.

Bone mineral density peaks around the third decade of life, and progressively decreases in years after.

Epidemiology
Affects 1-in-4 women and 1-in-8 men over the age of 50 in Canada.

Fragility fractures represent over 80% of all fractures in menopausal women over age 50.

== Risk Factors ==
 * Age >65 years
 * Fragility fracture
 * Prolonged use (>3 months in previous year,) of glucocorticoids (prednisone-equivalent dose of 7.5mg daily)
 * Use of other high-risk medications (androgen deprivation, aromatase inhibitors)
 * Parental history of hip fracture
 * Rheumatoid arthritis
 * Smoking
 * High chronic alcohol intake (>3u/day)
 * Low body weight (<60kg) or major weight loss (>10% of body weight at age 25)
 * Hypogonadism or premature menopause (<45yr)
 * Malabsorption syndrome, primary hyperparathyroidism, other disorders associated with rapid bone loss

Screening & Diagnosis
Anybody over the age of 50 needs to be assessed for risk factors of osteoporosis. This includes taking a thorough history to elicit any relevant risk factors (as listed above), as well as a physical exam.

Clinical screen for vertebral fractures:
distance < 2 fingers’ breadth
 * Measure height annually: prospective height loss > 2 cm or > 6 cm by patient’s recall
 * Measure rib to pelvis
 * Detect early kyphosis (occiput-to-wall distance > 5 cm)
 * Assess fall risk

Bone Mineral Density scan
High specificity, low sensitivity for predicting fracture risk.

Indicated in all adults after the age of 65. Also indicated in post-menopausal women, or men over the age of 50 who who meet any of the risk factors above. Areas reported on BMD are hip, vertebra, forearm and proximal humerus.

Osteoporosis is defined as an area of bone with a density that falls 2.5 standard deviations (DEXA T-score <-2.5) below the average peak bone mass for young adults.
 * Normal bone density - DEXA T-score ≥ -1.0
 * Reduced bone density (previously “osteopenia”) - DEXA T-score between < -1.0 and -2.5
 * Osteoporosis: DEXA T-score ≤ - 2.5
 * Severe OP: OP plus hx of fragility fracture.

FRAX and CAROC scoring
The issue with the above definition for osteoporosis is that in a elderly patient, a DEXA T-score of <-2.5 can actually indicate higher than average BMD for age. This also does not provide any sort of consensus towards how prone a patient would be to suffering a fragility fracture. As such, the updated Canadian osteoporosis guidelines now recommend calculating fragility fracture risk with one of two tools:
 * CAROC – Canadian Association of Radiologists and Osteoporosis Canada, used by radiologists on reporting BMD results.
 * FRAX – developed by WHO and adapted and validated to a Canadian population.

FRAX

 * Factors several risk factors:
 * gender, age, BMI, prior fracture, parental hx of hip fracture
 * prolonged glucocorticoid use, current smoking, high alcohol intake
 * rheumatoid arthritis, secondary causes of osteoporosis
 * Can be used without a BMD result; femoral neck BMD usually is included in the calculation, but is optional
 * Direct link for online Canadian FRAX tool

==== CAROC ==== 10 year CAROC risk of fragility fracture is reported in terms of risk categories:
 * Basal risk obtained from age, sex and femoral neck DEXA T-score on BMD.
 * Prior fragility #s after 40 and prolonged systemic glucocorticoid use increases basal risk one category.
 * 90% concordance with FRAX
 * An online summary of the CAROC risk categories is available at here.
 * Low risk: 10-year risk < 10%
 * Moderate risk: 10-year risk 10-20%
 * High risk: 10-year risk > 20% for major osteoporotic or > 3% for hip fracture.

Other investigations

 * Calcium
 * CBC
 * Creatinine
 * Alkaline phosphatase
 * TSH
 * SPEP (with vertebral fractures)
 * Vitamin D level

Non-pharmacological

 * Weight-bearing and strength-training exercises are beneficial in developing and maintaining bone integrity.
 * Resistance training and core exercises are recommended for stability in people with vertebral fractures.
 * For those patients with increased falls risk, consider gait training and balance exercises.

Vitamin D supplementation

 * Healthy adults < 50yrs: 400 – 1000 IU daily
 * Adults > 50yrs: 800 – 2000 IU daily
 * An optimal serum level is >75nmol/L, should check no later than 3 months post commencement
 * Best ingested with the fattiest meal of the day (absorbed with fat via the lymphatics)

Calcium supplementation

 * For adults >50yrs:1200 mg calcium daily through diet and supplements
 * Osteoporosis Canada’s website provides an online calcium calculator for calcium intake:
 * http://www.osteoporosis.ca/osteoporosis-and-you/nutrition/calciumrequirements/
 * Calcium is best absorbed with food, facilitated by stomach acid. It is most effective to break up the intake into two doses (lunch and supper)

Bisphosphonates

 * Acts on osteoclasts to inhibit bone resorption
 * 1st line treatment for patients at high risk of fracture
 * Alendronate (Fosamax) comes in daily (10mg) and weekly (70mg) formulations
 * Risedronate (Actonel) comes in weekly (35mg) and monthly (150mg) formulations
 * Zoledronic Acid (Aclasta) is available in yearly IV injections (5mg)
 * Main side effects are GI related – nausea, abdominal pain, heartburn, esophageal irritation, loose bowel movements.
 * Poorly absorbed, so should only be taken on an empty stomach with water.

Denosumab (Prolia)

 * Mechanism of action: Monoclonal antibody to the RANK-RANK ligand interaction – inhibits development and activation of osteoclasts
 * Trials have mostly shown benefit in women – trials in men still ongoing
 * 1st line for patients at high risk of fracture who have failed other therapies
 * Side effects include MSK pain, skin irritation/erythema, increased risk of cellulitis and rare reports of osteonecrosis of the jaw.

Hormone Therapy and SERMs (selective estrogen-receptor modulators)

 * SERMS
 * Postmenopausal women at high risk of vertebral fractures – no evidence of benefit in reducing non-vertebral fractures or hip fractures.
 * Hormone therapy
 * Perimenopausal women at high risk of fractures, with coexisting severe menopausal symptoms
 * Increased risk of venous thromboembolic events.

Teriparatide (Forteo)

 * PTH analogue that activates osteoblasts and builds bone.
 * Indicated in the most severe cases of OP, or in cases of OP where the patient is required to be on chronic glucocorticoid use


 * After the 24 months of treatment, it must be followed by an anti-resorptive agent (eg. a bisphosphonate) to sustain the newly remodelled bone.
 * Dose: 20mg sc daily, costs ~$9000 annually.

Calcitonin

 * 1st line for patients with pain from acute vertebral fracture
 * Only osteoporosis drug approved for women of child bearing age.
 * 200IU intranasal spray daily

Follow Up

 * BMD q1-3 years, depending on risk.
 * Duration of bisphosphonate therapy is controversial
 * Recent systemic review suggests no clear benefit in continuing therapy after 5 years, but no consensus exists currently, as longer studies are required.
 * If placed on Forteo, should repeat a BMD 24 months after initiation of treatment.