Osteoporosis

Author: Dr Nelson B. Watts University of Cincinnati 2008-10-29

Osteoporosis:  Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.

INTRODUCTION

 Definition.  Osteoporosis is defined as “a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.  Bone strength reflects the integration of two main features:  bone density and bone quality.”(1)  The concept of “bone quality” captures other properties of bone, such as microarchitecture, geometry and material properties, that, in addition to bone mass or density, contribute to bone strength.  Bone mineral density (BMD) measurement remains the best tool for diagnosing osteoporosis and assessing fracture risk; however, clinical tests to measure other bone properties are currently under development. 

          
Importance and impact. Osteoporosis is a ‘silent condition’ – no one can tell from how they feel if their BMD is good or bad or if it’s increasing or decreasing.  The importance of osteoporosis lies in the predisposition for fractures – broken bones – in the spine, hip, wrist and other sites. ‘Osteoporotic’ fractures or ‘fragility’ fractures are those that occur with day-to-day activities, although there is evidence that older adults who have ‘traumatic’ fractures also have skeletal fragility.  Approximately 2 million fractures due to osteoporosis occurred in 2005 at a cost of almost $17 billion.(2) Among women age 50 and older, osteoporotic fractures are more common than stroke (373,000 per year), heart attack (345,000 per year), and breast cancer (213,000 per year) combined.        

 For postmenopausal Caucasian women, a World Health Organization (WHO) Working Group defined osteoporosis based on BMD levels, expressed as “T-scores” (Table 1).(3)  

Table 1. World Health Organization (WHO) classification
 

Classification	T-score*
Normal	-1.0 or above
Low bone mass (osteopenia)	Between -1.0 and -2.5
Osteoporosis	-2.5 or below

The T-score compares a person’s BMD with the average value for healthy young people (age 25-30) and expresses the difference as a standard deviation score.  (One standard deviation is about 10% to 15% of the young-adult value.   

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T-scores for women are calculated using normal values for young Caucasian women.)  A postmenopausal woman with a T-score of -1.0 and higher (one standard deviation below peak BMD levels or above) is considered normal.   A woman with a T-score of -2.5 or below has osteoporosis.  T-scores between -1.0 and-2.5 fall into a borderline category called “low bone density” or “osteopenia.”  (The risk of fracture across this broad range is so great that a single label [“osteopenia”] is inappropriate and does not work for individual patients.(4)) 

 The International Society for Clinical Densitometry (ISCD) recommends using the same T-score classification for men over age 50 (that is a man with a T-score of -2.5 or below has osteoporosis). (T-scores for men are calculated using normal values for young Caucasian men).  For premenopausal women, men under age 50 and children, Z-scores are used (the Z-score compares an individual with age-matched, sex-matched and race-matched norms and expresses the difference as a standard deviation score).

Impact and cost.  Estimates in 2000 suggest that approximately 10 million Americans have osteoporosis and another 34 million have borderline low bone mass (osteopenia).(5) Approximately 70% to 80% of the patients with osteoporosis are postmenopausal white women; however, osteoporosis occurs at all ages, in men as well as women, and in all racial and ethnic groups.  

Why is the skeleton important?  The skeleton is a living organ and has several functions.  It protects internal organs, anchors muscles to provide for locomotion, forms cavities (marrow) for blood formation, serves as a reservoir for minerals and supports the weight and structure the body. Cortical bone or compact bone makes up the shafts of the long bones and the outer envelope of all bones.  Cancellous or trabecular bone, made up of struts and plates, makes up the inner parts of the vertebrae and the ends of the long bones. Bone tissue is made up of a protein matrix (90% collagen), mineral (hydroxyapatite -- calcium and phosphorus), and cells including osteoclasts (responsible for bone resorption or removal), osteoblasts (responsible for new bone formation), and osteocytes (responsible for regulation of remodeling and communication among cells). Bone remodeling is a process by which old bone is removed and replaced with new bone.  About 10% of the adult skeleton is replaced every year.  After about age 35 or so there is an imbalance between resorption and formation, so more bone is removed than is formed, leading to bone loss.

In both men and women, bone loss begins within a decade of two of skeletal.  Age-related bone loss averages about 0.5% per year.  With estrogen deficiency (menopause), accelerated bone loss begins (1% to 2% per year) and goes on for 5 to 10 years.  The average woman loses 20% of spinal bone mass between the ages of 40 and 70. 

Osteoporosis then, is inevitable if one lives long enough.  It comes early if peak bone mass is low or if bone loss is accelerated.  Peak bone mass is largely determined by genetic factors (sex, race, and other).  Fulfilling one’s genetic potential depends on getting enough calcium and vitamin D and staying physically active, as well as avoiding negative factors such as cigarette smoking, excessive alcohol, as well as diseases, conditions and medications that can lead to bone loss (Table 2).  With aging, there is decreased vitamin D activity, decreased intestinal calcium absorption, decreased calcium intake, decreased weight-bearing exercise, decreased muscle mass, and decreased sex hormones, all contributing to age-related bone loss.

Whites and Asians are more commonly affected than Hispanics and Blacks, again because of lower peak bone mass. However, men are also affected, other ethnic groups are also at risk and even young people can develop osteoporosis. 

Table 2.  Some diseases and conditions associated with low bone mass or rapid bone loss (secondary causes of osteoporosis).

• Digestive diseases (e.g., malabsorption, celiac disease, inflammatory bowel disease, severe liver disease)

• Nutritional disorders (e.g., anorexia nervosa, vitamin D deficiency
• Endocrine diseases (e.g. Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, hypogonadism, hypercalciuria) 
• Inflammatory disorders (e.g., rheumatoid arthritis)
• Genetic disorders (e.g., osteogenesis imperfecta, homocystinuria)
• Malignancies (e.g., metastatic carcinoma, multiple myeloma)
• Marrow-based disorders (e.g., mastocytosis, Gaucher’s disease
• Medications (e.g., prednisone and other glucocorticoids, excessive doses of thyroid hormone, anti-epilepsy drugs, DepoProvera, GnRH agonists, aromatase inhibitors, heparin, thiazolidinediones, selective serotonin reuptake inhibitors, proton pump inhibitors)

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DIAGNOSIS OF OSTEOPOROSIS

 Bone loss is silent; there are no symptoms from low bone mass or from ongoing bone loss. The diagnosis of osteoporosis is made either from the results of BMD testing or because of the occurrence of a fracture.  The “gold standard” for BMD testing is dual-energy x-ray absorptiometry (DXA) of the central skeleton (referred to “central DXA”).(6) This technique is widely available in the US.  The patient lies on a table; under the table is an x-ray tube that generates two different wavelengths of x-ray with different characteristics depending on the density of the tissue.  Above the patient is a detector that measures how much x-ray gets through the patient; what is absorbed is proportional to the density of the tissue. Spine and hip DXA can be used to diagnose osteoporosis, assess fracture risk and to monitor patients’ response to treatment.  Below is a print-out from a DXA BMD test.

          
BMD is reported in units of bone mineral content (BMC) in grams per two-dimensional area (cm squared).  Results are often expressed as “T-scores,” as described above.  For each standard deviation reduction in BMD there is about a 2-fold increased risk of fracture.(12) The association between low BMD and increased fracture risk is continuous, not absolute.  This means that there is no true “fracture threshold” and that the WHO cut point of -2.5 SD to define osteoporosis, which is arbitrary, should not be applied rigidly.

 Other BMD testing techniques

The International Society for Clinical Densitometry says that only central DXA should be used with the WHO criteria for osteoporosis, but other techniques are available for bone density testing.

 Quantitative computed tomography (QCT) measures trabecular and cortical BMD at several sites in the body, but is most commonly used to measure trabecular BMD in the spine. It may be used as an alternative to DXA for spine and hip measurements, but T-scores are often lower with QCT than with DXA.

 Low-cost, portable, devices can be used with to measure peripheral skeletal sites (e.g., wrist, forearm, finger, heel) to assess fracture risk. These devices use a variety of techniques (DXA, quantitative ultrasound, radiographic absorptiometry, radiogrammetry). Peripheral measurements provide reasonable assessment of fracture risk.  Again, T-scores calculated for the peripheral devices have different implications for fracture risk and for prevalence of low bone mass than measurements at central sites.  Also, because peripheral sites do not change much with treatment, they are not used for monitoring.(7)

Who should have a bone density test? The National Osteoporosis Foundation (NOF) recommends BMD testing for all postmenopausal women.  Women who are healthy and have no risk factors should be tested at age 65; younger postmenopausal women who have risk factors should be tested at the time of menopause or when the risk factor is recognized.  Risk factors that would indicate a need for earlier BMD testing include a family history of osteoporosis, a personal history of low trauma fracture as an adult, current cigarette smoking, and low body weight (Table 3).(9)  The ISCD recommends BMD testing in men at age 70 and for younger men at increased risk of fracture. 

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Table 3. National Osteoporosis Foundation (NOF) recommendations for BMD testing.(11)

• Postmenopausal women age 65 and older who have not had a prior BMD test.
• Postmenopausal women under age 65 who have one or more risk factors for osteoporosis* (including conditions known to cause osteoporosis).

 *Risk factors include personal history of fragility fracture as an adult, history of fragility fracture in a first degree relative, low body weight (<127 lbs.), current cigarette smoking, certain chronic diseases or the chronic use of certain medications (see Table 2)

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 Osteoporosis should be suspected in adults who fracture after age 45 or 50 and in patients with diseases, conditions, or medications that might cause bone loss (Table 2).  Patients who have had “subclinical” vertebral fractures may complain of back pain, easy fatigue, and early satiety (the stomach fills up quickly and appetite is lost -- due to crowding of internal organs).  On physical examination they may have height loss, kyphosis (”dowager’s hump”) or scoliosis (curvature of the spine).

APPROACH TO THE PATIENT AND TREATMENT

The main goal of management of osteoporosis is prevention of fractures.  For patients who have low bone mass but have not yet had fractures, the goal is prevention of the first fracture.  For the patient who already has had one or more fractures, intervention is urgently needed to prevent subsequent fractures.

 
A healthful life style is appropriate for everyone, whether they have osteoporosis or not.  Important factors for bone health include adequate intake of calcium and vitamin D, an active life style, including regular weight-bearing exercise and avoidance of cigarette smoking and other negative factors (Table 4).

Table 4.  Lifestyle measures for bone health and management of osteoporosis.

• Calcium intake of 1,200 mg daily (diet, plus supplement if needed)
• Vitamin D, 1,000 to 2,000 IU daily, sufficient to achieve a blood level of 25-hydroxyvitamin D between 30 and 60 ng/mL
• Weight-bearing exercise, if possible (e.g., walking at least 40 minutes a session, at least 4 sessions a week)
• Avoid cigarette smoking and other negative factors such as high intake of alcohol, caffeine, phosphorus, etc.
• Avoid falling and injury 

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The recommended intake of calcium is 1,200 mg daily for men and women over age 50.  Because the typical postmenopausal woman gets only 500 to 600 mg of calcium daily from dietary sources, calcium supplementation (500-1,000 mg daily) is often advisable.  With regard to the choice of calcium supplement, calcium carbonate is often preferred because it is inexpensive and effective (most reliable when taken with meals) but causes digestive difficulties (e.g., gas, constipation) in about 20% of people.  Those who have digestive problems with calcium carbonate can usually tolerate calcium citrate.

 Vitamin D is essential for the absorption and assimilation of calcium and has some direct effects on bone remodeling and direct or indirect effects on muscle strength and balance.  Recent studies suggest that vitamin D deficiency is common, especially among the elderly.(8) Supplementation with 1,000 to 2,000 IU of vitamin D per day may be required to achieve adequate blood levels of 25-hydroxyvitamin D (most supplemental multivitamin tablets contain 400 IU of vitamin D, but supplements of 1000 IU are available without a prescription). 

Weight-bearing exercise, such as walking or low-impact aerobics, is advisable. Patients should try to walk for 40 minutes or more, four times a week, if possible. Carrying light weights (one or two pounds) when walking is desirable.  Spinal resistance exercises may be helpful.  Balance, flexibility and strength training can improve strength, increase agility and reduce the risk of falls and fractures.

 Because most osteoporotic fractures involve some element of trauma or falling, patients who have osteoporosis should be counseled to reduce their risk of falling and to avoid activities that produce undesirable forces on the skeleton (e.g., pushing, pulling, bending, and lifting). 

Possible consequences of fracture include acute and chronic pain, changes in appearance (height loss, kyphosis), depression, dependence and deconditioning.  If present, these problems need to be identified and treated.  If the patient has pain, it is important for both the patient and the provider to understand that osteoporosis is not the cause of the pain, and that treating the underlying osteoporosis is not likely to relieve it.

 Diseases or conditions that might contribute to bone loss should be corrected if possible.

PRESCRIPTION DRUGS

Several prescription medications have been shown to reduce the risk of osteoporotic fractures significantly in women who have already had a fracture and in women who have low BMD (T-score -2.5 and below) but have not yet fractured.  Drugs have also been shown to prevent bone loss in recently menopausal women, to increase bone density in men and in patients receiving glucocorticoid treatment.  Agents approved by the US Food and Drug Administration (FDA) for prevention and/or treatment of osteoporosis as of 02/2008 are shown in Table 5.

Table 5.  FDA-approved medications for use in osteoporosis as of March 2008.

	Postmenopausal osteoporosis		Glucocorticoid-induced osteoporosis		Men
Drug	Prevention	Treatment	Prevention	Treatment
Estrogen (a)	x
Calcitonin (b) (Miacalcin®, Fortical®)		x
Raloxifene (c) (Evista®)	x	x
Alendronate (d)(i) (Fosamax®)	x	x		x	x
Risedronate (e)(i) (Actonel®)	x	x	x	x	x
Ibandronate (f)(i) (Boniva®)	x	x
Zoledronic acid (g)(i) (Reclast®)		x
Teriparatide (h) (Forteo®)		x			x

(a)     Estrogen is available as multiple brands and formulations, oral, transdermal, and injectable. Risks and benefits are beyond the scope of this discussion.

(b)     Calcitonin is available as a nasal spray.  The approved dose is 200 Units (one spray) daily, alternating nostrils.  Side effects include nasal irritation and note bleeds.

(c)     Raloxifene is available as an oral 60 mg tablet.  The approved dose is one tablet daily.  It can be taken without regard for food, time of day, or other medications.  Side effects include menopausal symptoms (hot flashes and night sweats), leg cramps, and blood clots.  Evista® is also approved to reduce the risk of breast cancer in women at increased risk.

(d)     Alendronate is available as daily doses of 5 mg (prevention of postmenopausal osteoporosis, treatment of glucocorticoid-induced osteoporosis in estrogen-replete women and men) and 10 mg (treatment of postmenopausal osteoporosis and glucocorticoid-induced osteoporosis in estrogen deficient women) and weekly doses of 35 mg tablets (for prevention of postmenopausal osteoporosis) and 70 mg tablets or liquid (for treatment of postmenopausal osteoporosis).  Alendronate 70 mg tablets are available as alendronate only or in combination with vitamin D 2800 or 5600 IU.  See note (i) for dosing instructions and side effects.

(e)     Risedronate is available as daily dosing of 5 mg tablets, weekly dosing of 35 mg tablets (both approved for all indications) and 75 mg tablets to be taken monthly 2 consecutive days (approved for treatment of postmenopausal osteoporosis).   See note (i) for dosing instructions and side effects.

(f)       Ibandronate is available as daily dosing of 2.5 mg tablets, monthly dosing of 150 mg tablets and intravenous dosing of 3 mg given IV every third month.  See note (i) for dosing instructions and side effects.

(g)     Zoledronic acid is available as a 5 mg vial for intravenous infusion given as an outpatient once yearly.  See note (i) for dosing instructions and side effects.

(h)     Teriparatide is available for daily subcutaneous self-injection in a pre-filled cartridge containing a 28 day supply. The dose is 20 micrograms daily.  Side effects include leg cramps, light-headedness, nausea, and elevations of blood calcium, usually mild.

(i)       Alendronate, risedronate, ibandronate, and zoledronic acid all belong to the same chemical class of agents, bisphosphonates.  Given by mouth, bisphosphonates are poorly absorbed under ideal conditions and not absorbed at all under less-than-ideal conditions (food and calcium block their absorption.  They must be taken on an empty stomach with water only, with nothing else by mouth for at least 30 minutes (60 minutes for monthly ibandronate).  Because oral bisphosphonates can irritate the esophagus, they should be taken with a glass of water (not a sip) and the patient should remain upright (seated, standing or moving around) until food has been taken.  Side effects include poorly-defined musculoskeletal complaints and rarely, osteonecrosis of the jaw.  Intravenous drugs in this class can cause an “acute phase reaction” with the first dose (fever and muscle aches), usually mild and temporary.  Bisphosphonates should not be given to patients with reduced kidney function.

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In February 2008, the National Osteoporosis Foundation (NOF) in the US published new Clinician Guidelines(9) with recommendations on whom should receive prescription drug therapy. Prescription medication is recommended for all patients who have hip or spine fractures, those with osteoporosis (a BMD T-score of -2.5 and below in the spine or hip – femoral neck or total hip), for patients whose T-score is between -1.0 and -2.5 who have fractured at other sites (besides hip and spine), who have a secondary cause of osteoporosis (such as glucocorticoid use – prednisone and similar medications – as well as other diseases and conditions that increase bone loss and/or fracture risk) and whose 10-year risk of fracture exceeds intervention thresholds.  Fracture risk can be estimated using a new tool called FRAX™ from the World Health Organization (www.shef.ac.uk/FRAX). The NOF thresholds for prescribing prescription drugs are 3% or more 10-year risk of hip fracture and 20% or more 10-year risk of major osteoporotic fracture (hip, upper arm, forearm or clinical spine fracture).

           

All but one of the current medications are considered “antiresorptive” agents – they work by reducing the removal of bone in the remodeling process.  They change the balance of remodeling to be more in favor of formation, which allows for improvement in the material properties of the bone tissue.  They also preserve microarchitecture. In most patients, they increase bone density, but the increase in bone density explains only a small proportion of the observed fracture risk reduction.

           

Teriparatide (Forteo®) is considered anabolic – a bone building medication.  It increases the number of bone-forming cells and stimulates the activity of existing bone-forming cells.  It improves microarchitecture and bone geometry.  In most patients, it increases bone density, on average, even more than the anti-resorptive medications.  However, with teriparatide, the increase in bone density also explains only a small proportion of the observed fracture risk reduction. 

           

Although the effects of an anabolic agent are theoretically appealing, and there are differences among the anti-resorptive drugs, the choice of treatment should first consider the proven ability of the drug to reduce the risk of fractures. There are no head-to head trials of any of these agents with fracture as an end-point.  Vertebral fractures are the most common consequence of osteoporosis, and all of the approved agents have proven effectiveness in this regard, though the evidence is stronger for some than for others.  However, only about 1 of 3 vertebral fractures are recognized at the time they occur, and only about 10% require hospitalization.  Nonvertebral fractures (literally any site outside the vertebra, but especially leg, arm, and pelvic fractures), especially hip fractures, cause the most morbidity and mortality, and incur the most cost.  Only 4 of these agents (alendronate, risedronate, zoledronic acid and teriparatide) have evidence for reducing the risk of nonvertebral fractures and only 3 (alendronate, risedronate and zoledronic acid) have evidence for reducing the risk of hip fractures.  Table 6 shows the evidence for fracture reduction for the agents approved to treat postmenopausal osteoporosis.

Table 6.  For FDA-approved medications approved to treat postmenopausal osteoporosis as of March 2008, evidence for fracture reduction.

Drug	Vertebral Fracture	Nonvertebral Fracture	Hip Fracture
Calcitonin (Miacalcin®, Fortical)	x	No effect demonstrated	No effect demonstrated
Raloxifene (Evista®)	x	No effect demonstrated	No effect demonstrated
Alendronate (Fosamax®)	x	x	x
Risedronate (Actonel®)	x	x	x
Ibandronate (Boniva®)	x	No effect demonstrated	No effect demonstrated
Zoledronic acid (Reclast®)	x	x	z
Teriparatide (Forteo®)	x	x	No effect demonstrated

           

Combining two anti-resorptive agents is not recommended.  Slightly greater gains in bone density are unlikely to provide additional fracture reduction, certainly not enough to justify increasing the cost and potential for side effects.  Likewise, combining an antiresorptive agent with teriparatide is not recommended, and may result in a “blunting” of the anabolic (bone-building) effect.  However, teriparatide should not be given for longer than 2 years, and should be followed by an antiresorptive agent to preserve the benefits.

MONITORING THE EFFECTS OF TREATMENT. 

Patients on treatment should have their height measured yearly (height loss could indicate vertebral fractures that may have otherwise gone undetected) and should report any fractures to their treating physician.  BMD testing is recommended every 1 to 2 years.  Stable or increasing bone density indicates good response to treatment.  Patients who have significant loss should be re-evaluated for underlying diseases or conditions.  A bone resorption marker may be helpful in deciding whether or not to change therapeutic agents.

           

MORE SOPHISTICATED TREATMENTS AND REFERRALS          

For patients who have painful or deforming vertebral fractures, vertebroplasty and kyphoplasty are procedures that offer options for relief of pain and possibly reversal of deformity.(10) These procedures, which involve injection of bone cement into an involved vertebra under radiologic guidance, have not been fully evaluated for long-term safety and efficacy.  They should be offered only to selected patients and should only be performed by experienced operators.

           

Osteoporosis can often be managed by primary care physicians.  The American Association of Clinical Endocrinologists has provided guidelines for referral of patients with osteoporosis for evaluation and/or management by a specialist in osteoporosis and metabolic bone disease.  These are shown in Table 7.

Table 7.  When to consider referral to an osteoporosis specialist.(9)
 

•  Patients who have osteoporosis of unexpected severity, with unusual features, or unusual underlying cause

• Patients with very low BMD (e.g., T-score -3.0 or below or Z-score -2.0 or below
• Young men or women (premenopausal) with osteoporosis
• Patients who fracture despite BMD that is only borderline low or normal

•  Patients with suspected or known underlying cause, particularly endocrine disorders (e.g., hyperthyroidism, hyperparathyroidism, hypercalciuria, Cushing's syndrome, hypogonadism, etc.) (see Table 2)
•  Patients who might be candidates for combination drug therapy
• Patients who are intolerant of approved therapies
• Patients who may be failing to respond to treatment
• Women taking estrogen who have with low baseline BMD
• Patients who have been on treatment who show apparent loss of BMD on serial studies or elevated bone resorption markers
• Patients who have fractures despite being on treatment

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SUMMARY

           

Osteoporosis is a common and costly condition that can cause disability or death.  Osteoporosis can be diagnosed based on the presence of a fragility fracture or, in postmenopausal women and men over age 50 without fracture who have BMD levels 2.5 standard deviations or more below the young normal mean. BMD testing is recommended for all women age 65 and older, for men age 70 and older, and for younger men and women who have risk factors.   Once osteoporosis is diagnosed and treatment contemplated, laboratory testing for possible secondary causes should be done.  Measurement of biochemical markers of bone turnover, particularly collagen cross links, may add some information.  Adequate calcium, vitamin D, and weight-bearing exercise are important for everyone and are fundamental to any program for prevention of bone loss or treatment of osteoporosis.  Effective prescription drugs are available for prevention of bone loss in recently menopausal women and for treatment of established osteoporosis.  Prescription mediation is indicated for men or women who have osteoporosis, defined either as a fracture or BMD T-score of –2.5 and below.  Frail older patients may be at risk of fracture because of poor eyesight, poor hearing, poor balance or muscle weakness, and benefit from balance and gait training, assistive aids, and physical therapy. 

Reference List

1. NIH Consensus Development Panel on osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285:785-795.

2. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007; 22:465-475.

3. Kanis JA, Melton LJ, III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137-1141.

4. Watts NB. What is osteopenia and what should be done about it? Cleveland Clinic J Med 2006; 73:29-32.

5. Bone Health and Osteoporosis: A Report of the Surgeon General. Washington, DC: US Government Printint Office, 2004.

6. Watts NB. Fundamentals and pitfalls of bone densitometry using dual-energy x-ray absorptiometry (DXA). Osteoporos Int 2004; 15:847-854.

7. Bracker MD, Watts NB. How to get the most out of bone densitometry. Postgrad Med 1998; 104:77-86.

8. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266-281.

9. Clinician's Guide to Osteoporosis. National Osteoporosis Foundation . 2008. available at www.nof.org.

10. Watts NB, Harris ST, Genant HK. Treatment of painful osteoporotic vertebral fractures with percutaneous vertebroplasty or kyphoplasty. Osteoporos Int 2001; 12:429-437.