Osteoporosis

As defined by the National Osteoporosis Foundation:

Osteoporosis, or porous bone, is a disease characterized by low bone mass and [microarchitectural] structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures, especially of the hip, spine and wrist, although any bone can be affected.

The increase in fragility results from both low bone mass and impaired bone quality.

Emphasizing the factor of ‘bone strength’, a factor in addition to and distinct from low bone mass, and the consequent increase risk of sustaining a fracture, a National Institutes of Health (NIH) Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy has defined osteoporosis in 2001 as

a skeletal disease characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality...

Primary osteoporosis can be of two major types: postmenopausal osteoporosis (osteoporosis, postmenopausal) and age-related or senile osteoporosis."

Osteoporosis, which literally means "porous bone", is a disease in which the density and quality of bone are reduced. As the bones become more porous and fragile, the risk of fracture is greatly increased. The loss of bone occurs "silently" and progressively. Often there are no symptoms until the first fracture occurs. —The International Osteoporosis Foundation (IOF)

Osteoporosis means “porous bone.” If you look at healthy bone under a microscope, you will see that parts of it look like a honeycomb. If you have osteoporosis, the holes and spaces in the honeycomb are much bigger than they are in healthy bone. This means your bones have lost density or mass. It also means that the structure of your bone tissues has become abnormal. As your bones become less dense, they become weaker. —The National Osteoporosis Foundation

Although more common in women, osteoporosis may occur in males.

Clinical practice guidelines are available from both non-specialty organizations and specialty societies.

Pathogenesis of osteoporosis

Current concepts of osteoporosis pathogenesis contend that numerous mechanistic factors concentrate on bone in causing reduction of the mass of bone, and architectural—microarchitectural—degeneration of the structure of bone, resulting in a weakening of bone strength that increases the risk of fracture from physical trauma that might otherwise not fracture the bone.

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures...the fundamental pathogenetic mechanisms underlying this disorder...include:

   (a) failure to achieve a skeleton of optimal strength during growth and development;

   (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and,

   (c) failure to replace lost [resorbed] bone due to defects in bone formation.

Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility.<

One of every eight hip fractures may be due to smoking of tobacco.

Subclinical hypercortisolism may underlie about 5% of cases of osteoporosis. These patients can be identified by serum cortisol levels greater than 50.0 nmol/L after a 1-mg overnight dexamethasone test.

Glucocorticoid drugs can cause osteoporosis.

Diagnosis

Diagnosis is made be bone densitometry, or by the presence of fragility fractures. However, high-trauma fractures also are associated with osteoporosis.

History and physical examination

A systematic review by the Rational Clinical Examination concluded that the best physical findings in women are:

• weight less than 51 kg
• tooth count less than 20
• rib-pelvis distance less than 2 finger breadths
• wall-occiput distance greater than 0 cm
• self-reported humped back

For men, the "MORES" clinical prediction rule uses age, weight, and history of chronic obstructive pulmonary disease to predict risk of a fracture with a number needed to screen of 279 to prevent one fracture:

• sensitivity = 93%
• specificity = 59%

Bone densitometry

Densitometry using photon absorptiometry is scored by two measures, the T-score and the Z-score. Scores indicate the amount one's bone mineral density varies from the mean. Negative scores indicate lower bone density, and positive scores indicate higher.

T-score

The T-score is a comparison of a patient's bone density to that of a healthy thirty-year-old. The criteria of the World Health Organization are:

• Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty year old woman.
• Osteopenia is defined as less than -1.0 and greater than -2.5
• Normal is a T-score of -1.0 or higher

Z-score

The Z-score is a comparison of a patient's bone density to the average bone density of their, sex, and race. This value is used in premenopausal women, men under aged 50, and in children.

Other tests

Screening patients for hypercortisolism with a 2-day, low-dose dexamethasone suppression test ( 0.5 mg of dexamethasone by mouth every 6 hours followed by measurement of serum cortisol at 9:00 a.m. 2 days after the first dose), may identify hypercortisolism in 10% of patients who have both T-scores of –2.5 or less and vertebral fractures.

Screening

Females

The U.S. Preventive Services Task Force, originally in 2002 with 2010 update, recommends screening women if:

• women aged 65 years or older

Interval for repeating screening is uncertain.

Tools for assessing risk include:

• Osteoporosis Risk Assessment Instrument (ORAI) (not mentioned by USPSTF)
• FRAX (mentioned by USPSTF)

The National Osteoporosis Foundation recommends screening women if:

• 65 years of age or older
• "Women in the menopausal transition if there is a specific risk factor associated with increased fracture risk such as low body weight, prior low-trauma fracture or high risk medication"
• Fracture after age 50
• "A condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for ≥ three months) associated with low bone mass or bone loss"
• Low body weight

Clinical prediction rules for osteoporosis

	Outcome	Sensitivity	Specificity	For 5% prevalence of osteoporosis as reported by WHI
				Positive predictive value	Negative predictive value
QFracture QFracture ...	...	...	...	...
Women’s Health Initiative (WHI) Hip Fracture Risk Calculator > 1% estimated risk of fracture (≥ 18 points)	• T-score < –2.5 SD by photon absorptiometry • Fracture (using ≥ 21 points)	22% 50%	96% 85%	22%	4.1%
Osteoporosis Self-Assessment Tool (OST) < 2	• T-score < –2.5 SD by photon absorptiometry at femoral neck or lumbar spine	69%	59%	8%	2.7%
Osteoporosis Risk Assessment Instrument (ORAI) ≥ 9	• T-score < –2.5 SD by photon absorptiometry at femoral neck or lumbar spine	64%	59%	8%	3.1%
	• T-score < –2.5 SD by photon absorptiometry at femoral neck	98%	28%	7%	0.4%
Body weight < 70 kg	• T-score < –2.5 SD by photon absorptiometry at femoral neck	87%	48%	8%	1.4%

Clinical prediction rules are available to guide selection of women for screening. The Osteoporosis Self-Assessment Tool (OST) may be the most sensitive strategy for detecting abnormal bone density according to a meta-analysis in 2007. More recently, a clinical prediction rule for women developed from the WHI studies (http://hipcalculator.fhcrc.org/) is available to predict risk of a fracture over five years. Of note, the clinical prediction rule did not study the contribution of physical examination findings.

Unfortunately, all current guidelines and prediction rules ignore the role of risk factors for accidental falls.

Males

A cost-benefit analysis concluded that "bone densitometry followed by bisphosphonate therapy for those with osteoporosis may be cost-effective for men aged 65 years or older with a self-reported prior clinical fracture and for men aged 80 to 85 years with no prior fracture."

A clinical practice guideline and systematic review by the American College of Physicians recommends "clinicians obtain DXA [dual-energy x-ray absorptiometry] for men who are at increased risk for osteoporosis and are candidates for drug therapy." However, the College did not define increased risk.

Prevention and treatment

Clinical practice guidelines are available.

The National Osteoporosis Foundation recommends treating women if:

• T-score ≤ -2.5
• Low bone mass (T-score between -1.0 and -2.5) and ≥ 3% 10-year hip fracture probability. This threshold was determined by a cost-benefit analysis.

It is not clear which medications are best for treating osteoporosis.

In monitoring bone mineral density, the least significant change is defined as "defined as a change that is 2.8 times the precision error for each measured site, for each technologist, and it is best expressed as an absolute value (g/cm2)".

Special consideration is needed for patients taking glucocorticoids.

Calcium

A meta-analysis of randomized controlled trials concluded "Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation)."

Calcium supplementation may increase rates of myocardial infarction.

Vitamin D

Vitamin D is only effective if given with calcium. Vitamin D may also prevent accidental falls by increasing muscle strength.

Antiresorptive medications

Treatment may be worthwhile when the 10-year risk of hip fracture or major osteoporotic fracture are ≥3.0 or ≥20 percent, respectively.

Bisphosphonates

Bisophosphonates may be cost-effective when the 10 year risk of fracture is 3% (see osteoporosis#prognosis below). Once yearly, intravenous zoledronic acid reduced second hip fractures in a randomized controlled trial of women after an initial hip fracture. In this trial, 19 patients had to be treated for one hip fracture to be prevented.

Alendronate reduces clinical fractures by 36% in women with osteoporosis. The benefit is stronger for women with existing vertebral fractures.

The effects of alendronate may continue through 10 years of treatment according to the FLEX randomized controlled trial which included women with T-scores of -1.6 or worse. However, the FLEX trial found increased wrist fractures with long term treatment. This increase may be due to "oversuppressing bone turnover that could, potentially, impair some of the biomechanical properties of bone. High doses of bisphosphonates result in accumulation of microdamage in the bones of dogs, but the relevance of these findings in terms of bone strength and clinical use is unclear."

Selective Estrogen Receptor Modulators

Referred to as SERMs, selective estrogen receptor modulators....

Denosumab

Denosumab is a humanized monoclonal antibody that inhibits osteoclasts.

Anabolic medications

As opposed to antiresorptive drugs, anabolic drugs enhance bone formation.

Strontium Ranelate

Strontium Ranelate has both anti-resorptive and anabolic mechanisms.

Prognosis

A bone density of one standard deviation below age adjusted mean approximately doubles the risk of fracture.

After started treatment with a bisphosphonate it may not help to repeat measurements of bone density.

FRAX tool

Improvements in the prediction of hip fracture by adding the FRAX to the bone density.

	Sensitivity (taken from Table 1 of Johansson)	Specificity (calculated from Table 1 of Johansson)	Positive predictive value	Number with abnormal result needed to treat to prevent one fracture†
Bone density < unstated value	56%	79%	6%	47
Bone density plus FRAX > 3.7%	56%	84%	8%	33
† This is calculated by (100/(PPV*0.35) and assumes biphosphonate reduces fractures by 35% as found in the FIT trial.

The risk of fracture can be estimated by the Fracture Risk Assessment Tool (FRAX). This tool was recommended by the WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level during their 2004 meeting. Interpretation of the ability of the FRAX is hindered by their publications not following guidelines for reporting of studies of diagnostic tests as the STARD. In addition, development of the tool may be affected by conflict of interest. Also, the FRAX developers may have changed their calculations within the tool without publishing the changes or their reason.

The FRAX tool may not be better than using bone density and age alone.

QFracture

The QFracture tool (http://www.qfracture.org/) may be more accurate than the FRAX. However, QFracture does not incorporate bone density.

Repeat density testing

A cohort study suggests the following times to repeat densitometry depending on the following results for initial densitometry:

• Normal (T score, −1.00 or higher)- 15 years
• Mild osteopenia (T score, −1.01 to −1.49) - 15 years
• Moderate osteopenia (T score, −1.50 to −1.99) - 5 years
• Advanced osteopenia (T score, -2.00 to −2.49) - 1 year

National action plan

Washington, DC (May 21, 2009) – The National Osteoporosis Foundation (NOF) in conjunction with the National Coalition for Osteoporosis and Related Bone Diseases held a briefing on Capitol Hill today to engage Congress in an action plan for making bone health a national priority and encourage lawmakers to sign on to the “Bone Health Promotion and Research Act.

About Osteoporosis

According to NOF [National Osteoporosis Foundation], osteoporosis, often referred to as a “silent disease,” is increasing in significance as the population of our nation both increases and ages. The World Health Organization, the National Osteoporosis Foundation and the U.S. Surgeon General have officially declared osteoporosis a public health crisis. In fact, osteoporosis and associated fractures are a significant cause of mortality and morbidity.

— In the U.S. today, an estimated 10 million men and women suffer from osteoporosis
— Almost 34 million Americans are estimated to have low bone mass, placing them at increased risk for osteoporosis
— Broken bones due to osteoporosis are more common in women than breast cancer, heart attacks and strokes combined
— The impact of breaking a bone can be significant and often leads to a downward spiral for the patient

— By 2025, the annual direct costs of treating osteoporosis fractures in the US are estimated at $25 billion