Osteoporosis

Definition

Decrease in bone mineral density, or decrease in bone mass per unit volume.

The WHO consensus definition states that osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increased fracture risk.

Essentially, there is a decreased amount of normal bone. This is in contrast to osteomalacia where there is a normal amount of abnormal bone.

Peak bone mass

Peak bone mass is achieved between 20 and 30.  It is higher in males than females.

For each loss of one standard deviation from peak bone mass the risk of an osteoporotic fracture increases by 2-3 times.

The Gemini astronauts spent 90 days in space and came back with a loss of 22% of their bone from the os calcis (calcaneus).

Epidemiology

About 1/3 of women over 65 have osteoporosis.  10-20% of men have osteoporosis.

The lifetime risks for Caucasian women over 50 developing fractures are:

Vertebral              32%

Hip                       16%

Colles                   15%

Risk factors for low bone mass

1. Low body weight (less than 85% ideal)
2. Recent weight loss
3. History of fractures
4. Family history of fractures
5. Smoking – double risk of hip fracture at any age.

Pathology

Trabecular bone is lost before cortical bone.

Classification

There are two forms of osteoporosis:

Type I – estrogen related.  Affects particularly cancellous bone, and related to vertebral fractures.

Type II – senile osteoporosis.  Affects both cancellous and cortical bone, and related to hip fractures.  This is generally a form of low turnover osteoporosis (see below).

Diagnosis

Osteoporosis can be measured by measuring bone mineral density at different sites in the body.  It can be defined as a femoral neck BMD at least 2.5 standard deviations below the mean for young adult women.  Comparison with young women provides T scores.  Z scores are compared with patients of the same age. (Z is reaching the end).

If the bone mass is within 1 SD of normal, the patient is considered to have normal bone.

If the bone mass is within 1-2.5 SD the patient is considered to have osteopenia.

If the patient has a T score of less than –2.5 and a “fragility fracture” they are considered to have severe osteroporosis.

Diagnostic tools

Radiographic absorptiometry

1998 CCR states that the mean density of the middle phalanges of the second third and fourth fingers is calculated from a single XR of the hand along with an aluminium phantom, and the results are reported in aluminium equivalent values.  The technique is limited to the appendicular skeleton.

Single energy X-ray absorptiometry

Has replaced single energy photon absorptiometry.  This was an early version of the technique that used a photon source and emitted much more radioactivity.  Measures attenuation of I125 as it passes through the distal radius, or the calcaneus.  Not reliable for axial skeleton due to soft tissue absorption.  The measurements correlate well with the status of the peripheral long bones but poorly with the axial skeleton.

DEXA scanning (dual photon absorptiometry)

Has replaced dual energy photon absorptiometry.  Dual XR absorptiometry is the most sensitive means of diagnosing osteoporosis.  Radiation doses are very low (around 1/50^th the rate of a CXR) and scanning times are short.  A whole body scan takes only 4 minutes.  Bone mass is measured at the hip and the spine, and the lower figure is used to diagnose osteoporosis.  The figure at each site best predicts the chance of fracture at that site.   Major disadvantage of this technique is it doesn’t distinguish between cortical and trabecular bone.

Who should have a DEXA scan?  Peri and post menopausal women, patients with known metabolic bone disease and patients with a high number of osteoporosis risk factors.

Quantitative CT scanning

This gives a much higher dose of radiation, and is less sensitive than DEXA scanning.  However, it is the only method able to distinguish between cortical and trabecular bone.  The lumbar spine is scanned and compared with a hydroxyapatite phantom that is scanned concurrently.  Single and dual energy CT scanning is possible.  Dual energy is more accurate but at a higher radiation dose, so single energy is usually used.

QCT is also the only method that provides a direct measure of volume and hence density (g/cubic cm).

Ultrasound

This may become a screening tool.  Unfortunately, US of the calcaneus only moderately correlates with spine and hip bone mass.

Radiology

The main finding is thinning of the cortex.

One way to assess this is to look at the mid-diaphysis of the second metacarpal.  The cortex here is normally at least ¼ and sometimes 1/3 the total diameter of the bone at that point.  In osteoporosis this ratio is diminished.

There must be a loss of around 40% of cancellous bone for it to be detectable as osteoporosis.

Disuse osteoporosis can be aggressive and result in a diffuse permeative pattern throughout the cortex.  This can be confused with sinister lesions such as MM(myeloma), primary lymphoma of bone, or Ewing’s sarcoma.

Benign DDx are haemangioma and post radiotherapy changes.

Biochemical markers

Standard biochemistry is normal – normal calcium and phosphate.

Urinary collagen degradation products include N-telopeptide, pyridinoline and deoxypyridinoline peptides.  These are measure of the rate of bone resorption.  These are more sensitive than hydroxyproline measurements.  Hydroxyproline will pick up the larger bone turnover in Paget’s disease.

Carboxy terminal collagen cross links (a.k.a crosslaps) can be measured in the serum and provide a more specific measure of bone resorption.

Markers of bone formation include serum alkaline phosphatase and osteocalcin concentrations.

Other laboratory tests

Hyperthyroidism is a cause of secondary osteoporosis and patients should have their thyroid levels checked.

Males with osteoporosis should have their testosterone level checked, as osteoporosis caused by testosterone deficiency is treatable and reversible.

Treatment

To choose the correct form of treatment, the clinician must decide if the patient has primary or secondary osteoporosis, and whether the osteoporosis is a high or low turnover condition.

Secondary causes of osteoporosis include:

1. Endocrine
   1. Hyperthyroidism
   2. Hyperparathyroidism
   3. Type I diabetes
   4. Corticosteroid induced osteoporosis
2. Bone marrow abnormalities
   1. E.g. multiple myeloma
3. Osteomalacia 
   1. Found in 4-8% of patients with hip fractures in northern US hospitals
   2. Biochemical markers include low normal calcium and phosphate, low 25-hydroxy vitamin D, secondarily elevated PTH, elevated alkaline phosphatase.

Patients with elevated levels of collagen degradation products have high turnover osteoporosis.

Low turnover osteoporosis represents a failure of osteoblasts to form bone.

Prevention

1. Peak bone mass
   1. Encourage adequate calcium intake (1500mg day in young adults)
   2. Regular impact exercise
   3. Avoid anorexia
2. Balance
   1. Tai chi adherents have 25% fracture rate
   2. Dance is also helpful for balance

Antiresorptive agents

There are three main groups of antiresorptive agents:

1. Estrogens
2. Calcitonin
3. Bisphosphonates

Calcium and Vitamin D are weak antiresorptive agents.

Calcium

There is evidence for increasing rates of calcium deficiency in the community.

The overall recommended dose is 1500mg/day, which is difficult to achieve without supplementation.  Dietary sources include dairy food, broccoli, tofu and rhubarb.  Calcium supplements should be encouraged in girls during puberty and continued.

Calcium supplements are best absorbed if given throughout the day, with no more than 500mg at any one time.  Calcium carbonate contains 40% elemental calcium and needs acid to be absorbed, so should be given with food.

Calcium citrate doesn’t need to be taken with food and doesn’t have the same constipatory effects of calcium carbonate.

There is clear evidence that calcium supplementation is associated with decreased rates of bone loss.  It probably reduces fracture rates by around 10%.

It probably enhances the effects of estrogen and other antiresorptive agents.

Vitamin D

Vitamin D is obtained from the diet (vitamin D2, found in cod liver oil, fatty fish, milk, fortified cereals (Sardine sandwich and a glass of milk)) or from exposure of 7-dehydrocholesterol to sunlight (needs only 15 minutes exposure of face and hands to sunlight/day in whites).  The two sources are taken to the liver as cholecalciferol (Vitamin D3) where they undergo 25 hydroxylation to become 25 hydroxyvitamin D.  This is taken to the kidneys on an alpha globulin where it is converted to either 1,25 dihydroxyvitamin D or 24,25 dihydroxyvitamin D.  1-alpha hydroxylase activity is stimulated by PTH.

The active metabolite is 1,25-dihydroxyvitamin D (calcitriol).  Vitamin D is necessary for calcium resorption from the gut.  It increases phosphate resorption from the kidneys.

24,25 dihydroxyvitamin D influences growth plate chondrocyte maturation and is a potent mitogen in the proliferative zone.  It plays a role in bone formation and fracture repair.

In vitamin D deficient people (often seen in institutionalized patients) vitamin D supplementation will increase bone mass and decrease fracture rate.

Individuals should take between 400 and 800 units of Vitamin D daily.

Estrogen

Osteoblasts have receptors for estrogen.

Estrogen increases calcium absorption across the gut and conserves renal calcium.

When women enter menopause their bone mass decreases by 2% per year for 6-10 years.  Bone loss than plateaus out to the normal 0.5% p.a.

The administration of estrogen to women during the rapid perimenopausal bone loss period decreases bone loss in around 80% of patients, particularly in trabecular bone.  Women will actually gain bone mass, at around 2% per year.

Estrogen would be expected to decrease the fracture rate by 50-75% at 10 years.

Unfortunately, if estrogen is stopped there is a rapid catch up loss, so that 7 years after stopping therapy the bone mass approaches that of someone who has never taken estrogen.  Estrogen should thus be taken at the start of menopause and continued for the patient’s life.

The bone sparing dose is 0.625mg/d.  Estrogen works better when given with calcium.  If the woman still has a uterus, she must also be given progesterone.

Estrogen also has a beneficial effect on coronary artery disease, vaginal atrophy and hot flushes.  The main side effect is breast cancer.  Women taking HRT would expect to go from 11 cases of breast cancer per 100 to 14 cases of breast cancer per 100, however the overall survival rate is higher.

Estrogen is thus contraindicated in women with a strong family history of breast cancer, or a personal history of thrombophlebitis or strok

Selective estrogen receptor modulators

Recently two estrogen receptors have been defined.  One exists in breast tissue, and SERMS (prototype is raloxifene) have antiestrogen effects in breast tissue but pro-estrogen effects on the skeleton.

Raloxifene has been shown to decrease the risk of breast cancer by 50% compared with estrogens, but is not as effective as estrogen on the skeleton.

Calcitonin

This is a hormone that specifically binds to osteoclasts and decreases their activity and number. It is secreted by the parafollicular cells of the thyroid.  It is not thought to be physiologically important in humans.

Salmon calcitonin is more potent than human calcitonin but resistance can develop to it.  The usual dose of salmon calcitonin is 200u sprayed into alternate nostrils each day.

Calcitonin is the only antiresorptive agent to have an analgesic effect, and may be used in the early stages after a vertebral crush fracture.  It doesn’t appear to have any ill effects on fracture healing.

Calcitonin is particularly effective in augmenting cancellous bone, but hasn’t been shown to be of benefit in cortical bone.  It may decrease the vertebral fracture rate by around 40%.

Bisphosphonates

Bisphosphonates are synthetic analogues of pyrophosphate that bind to hydroxyapatite.  The linking oxygen of the pyrophosphate is substituted by a carbon and various side chains.

They work by binding to the surface of hydroxyapatite crystals and inhibiting their resorption, as well as by poisoning osteoclasts.

Alendronate (Fosamax) acts as an inhibitor of osteoclast mediated bone resorption. It increases bone mass in the hip and spine.  At 12 months there is on average a 3% increase in hip BMD and a 5% increase in lumbar BMD.  Black showed a 51% reduction in fracture risk at 3 years with a 10mg daily dose.  In patients that sustain a vertebral fracture the loss of height is less severe (5.9 vs 23.3mm).  There is evidence that bone mass continues to improve for 4 years after taking the drug.

1. The dose is 10mg daily or 70mg weekly.  The tablet is taken first thing in the morning, on an empty stomach, with a full glass of water, and the patient must then stand or sit upright for 30 minutes.
2. Calcium should be given concurrently
3. This costs the community around $840 per annum (2002)
4. The drug is distributed to the bone and the rest is excreted in the urine.
5. Side effects include peptic ulceration, reflux oesophagitis etc.  Patients need to stop taking the medication if they develop dysphagia, odynophagia or retrosternal pain. 
6. The bone formed in patients treated with alendronate is of normal quality
7. The half life of alendronate in the skeleton is 10 years.
8. Alendronate and estrogens may be synergistic.

Alendronate interferes with bone mineralization only at a dose 6000 times the dose that interferes with resorption, hence it has a very low chance of inducing osteomalacia.  This is opposed to etidronate, where the safety margin is one to one.

The use of alendronate along with HRT leads to significant increases in BMD cf either agent alone.

Alendronate prevents bone loss in post-menopausal women who do not have osteoporosis.

Bone stimulating agents

These agents would be most useful in low turnover osteoporosis.

These are currently experimental, but should be available soon.  They include:

1. Sodium fluoride
   1. Directly stimulates recruitment and differentiation of osteoblasts.
   2. Enhances bone mass, particularly trabecular bone
   3. Needs to be given with calcium
2. Cyclical parathyroid hormone
   1. Leads to increase in cancellous bone but a decline in cortical bone.