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Osteoporosis- Part II

(9/9/01)- Epidemiology:

30% of all post-menopausal Caucasian women will be diagnosed with osteoporosis

54% will have a low bone mass at the hip, spine or wrist

At the time of menopause, women begin a period of accelerated bone loss averaging 2-4% / year for the next ten years. This acceleration is greatest in the first 3-6 years, then gradually assumes the level of premenopausal loss (~1%/year). 10-15% of total bone loss is estrogen-dependent.

Pathophysiology:

Estrogen-deficiency mediated increase in the number of bone resorption units, as well as a focal imbalance between osteoclasts and osteoblasts at each site. Estrogen receptors have been identified on both osteoblasts and clasts.

Cancellous bone is more metabolically active then cortical bone, therefore it's mass and structural integrity is more severely affected by this process.

During the accelerated period of bone loss immediately post-menopausal, cancellous bone loss is increased three-fold - if the bone loss causes trabecular discontinuity, the structural integrity of the bone is irreversibly weakened.

Vertebrae have a high percentage of cancellous bone and are the first bone affected postmenopausally.

Who to test for bone mineral density - screening is only recommended if it will influence individual treatment decisions. If it will, consider it with;

All postmenopausal women over 65 who have one or more additional risk factors for osteoporosis besides menopause

All women over 65 regardless of additional risk factors

Postmenopausal women who present with fractures

Women who are considering therapy for osteoporosis, if Bone Mineral Density (BMD) testing would facilitate the decision

Women who have been on Hormone Replacement Therapy (HRT) for long periods

Bone Mineral Density:

T-Score (values given as per WHO Study Group) diagnostic categories:

Normal: BMD value within 1 standard deviation (SD) of the young adult reference mean

Low bone mass: BMD between 1 - 2.5 SD below young adult mean

Osteoporosis: BMD 2.5 SD below young adult mean

Note: T-scores vary by the instrument used to obtain the data; measurements for a given patient can vary up to 15% from manufacturer to manufacturer

Z-Score:

Compares BMD measurements in an age and sex-matched population. NOT used to define osteoporosis since doesn't reflect the increasing prevalence with age. Is used to prompt search for secondary cause.

BMD in African-Americans is about 10% higher then in people of European origin. There is also variation among other ethnic groups. Caution, therefore, with extrapolation of data to other pops since most studies have been done on Caucasian women.

Measuring bone density:

In vivo accuracy may be influenced by correction of overlying soft tissue and other artifacts that can complicate measurement of spine BMD.

There is discordance of BMD at different sites.

Except in certain cases (e.g. Pt receiving bisphosphonates or corticosteroids), slow rate of bone loss and lack of precision in measurement means significant changes in BMD can only be reliably measured over an interval of several years.

Vertebral body is the most helpful site to measure if you do serial measurements.

Serial measurements should, if possible, be performed using the same machine.

Dual X-ray Absorptiometry (DXA)

Most commonly used. Can measure central (hip/spine) and axial skeleton. Low radiation exposure.

May over-read density of bones if have compression fractures, osteophytes, or overlying bones.

Ultrasound Densometry (Ultrasonometry) of Bone

New entry in BMD measuring. No radiation. Can be performed in office.

Most commonly measures heel or tibia.

Normal bone shows higher attenuation, and is associated with greater velocity, compared to osteoporotic

bone. However, there is only modest correlation between this measurement and bone density

measurement at same site (r=0.7), suggesting this measures other properties, e.g. bone elasticity.

Bone turnover markers:

Adjunct to BMD screening: cannot be used to diagnose osteoporosis (cut-off points not established) or evaluate severity.

Possibly can be used for more immediate assessment of response to therapy

Other risk factors for fracture:

Non-modifiable

Personal history of fracture as an adult (esp. after 50 years of age)

History fracture in first-degree adult relative (esp. maternal)

Caucasian

Advanced age

Female

Lifelong low calcium intake

Potentially modifiable

Dementia/poor health/frailty

Current cigarette smoking

Low body weight (<127lbs)

Estrogen deficiency - early menopause, bilateral oopherectomy, prolonged premenopausal amenorrhea

Alcoholism

Recurrent falls

Inadequate physical activity/poor health/frailty

If a woman has >4 risk factors the incidence of hip fracture is 19 per 1,000 woman years compared to 1.1 per 1000 in women with two or fewer risk factors.

Note: secondary osteoporosis may be caused by a number of medications (including long-acting benzodiazepines, anticonvulsant, glucocorticoids) and medical conditions (including hyperparathyroid, excessive thyroid replacement, renal disease, malabsorption)

Drug Therapy:

Who to treat? - postmenopausal women who present with vertebral or hip fracture (treatment); women with BMD T-scores below -2 in the absence of risk factors, and BMD T-score <1.5 if have other risk factors (prevention)

There is no direct comparative data on the effectiveness of estrogen, bisphosphonates, Selective Estrogen Receptor Modifiers (SERM), and calcitonin in the treatment of osteoporosis. Therefore, it is not known which is more effective or which combo produces the best effect.

Must look at the other effects of the medications, the patient profile, and comorbidities.

Calcium (Ca) and Vitamin D:

Randomized trials suggested that dietary supplementation with both Ca and Vit. D in the elderly will result in an increase in bone mass and decrease in fractures

If more than 500 mg/d is used, dosage should be split to increase absorption

Ca is best given with food because the acid load of the meal provides better absorption.

Recommended adequate daily intake: 19-50 y.o. 1,000 mg/d, >51 y.o. 1,200 mg/day

Estrogen:

Clinical trails evaluating estrogen treatment dating back to the 70's show an association with stabilization or increase in BMD of 1-5% when initiated soon after menopause.

Prospective cohort study of 9,704 women showed for optimal anti-fracture effect estrogen treatment should be initiated within 5 years of menopause and be continued indefinitely.

Cross-sectional study 740 women suggests that late but long term use may be associated with preservation of bone mass (did not look at fracture outcome).

Evaluation of observational studies estimates that 5 years of HRT decreases the risk of vertebral fractures by 50-80%, and the risk of hip and wrist fractures by 25%. Based on studies of long-term use of HRT, 10+ years of treatment may be expected to decrease the rates of all fractures by 50-75%.

20% of women continue to have significant bone density loss despite taking estrogen

How long to treat with estrogen - once estrogen is stopped a rapid phase of bone loss, as is typically seen right after menopause (2-4%/yr), occurs. The difference between those who took estrogen and those who did not declines over time. This suggests that the benefit of short-term estrogen use is to delay the age at which osteoporosis is diagnosed.

Selective Estrogen Receptor Modulators (SERMs):

Clinical trials have shown that they prevent bone loss with an estrogen agonist effect on bone.

Results of controlled studies of raloxifene focusing on BMD, vertebral fracture incidence, and cardiovascular risk factors have shown similar effects as estrogen. However, raloxifene did not relieve vasomotor menopausal symptoms and was associated. with increased incidence of hot flashes.

Bisphosphonates:

Have strong affinity for hydroxyapatite, a major inorganic component of bone. They reduce the rate of bone turnover and inhibit osteoclasts.

Poorly absorbed. Must be taken on an empty stomach. Alendronate can cause esophagitis (as of 1996 there were 199/475,000reported cases) - take in AM and sit up for hr after dose. Alendronate is taken with water

Three generations, each with ten-fold antiresorptive potency

Alendronate - second generation. Recommended dosage 10mg everyday (qd) for treatment, 5mg qd for prevention. Large double-blind clinical trial to assess frequency of vertebral and non-vertebral fracture in post menopausal women with low bone mass concluded that concluded that 4 years of alendronate treatment increased bone density and decreased risk of vertebral fracture. Study showed it would take > 4 years to substantially reduce the risk of clinical fractures in women who do not have osteoporosis. In another study showed addition of alendronate to ongoing HRT shown to produce an increase in BMD beyond that of HRT alone, but not designed to study differences in fracture incidence.

Risedronate - third generation. Studies have shown it effective in preventing postmenopausal bone loss (by 76% with 5 mg qd), in reducing vertebral fracture risk with known osteoporosis (65% reduction in first year of treatment with 5 mg qd), and in reducing the risk of hip fracture in elderly women with osteoporosis by 40%.

How long to treat - Alendronate has a ten-year half-life. The accelerated bone loss observed with estrogen is not seen with discontinuation of alendronate. Intermittent therapy might be effective in maintaining BMD gains. With etidronate, after 5 years of use BMD was maintained for another 2 years after treatment was stopped.

Calcitonin:

A polypeptide hormone that plays a role in regulation of Ca and bone metabolism.

Continuous use is associated with persistent decrease in bone resorption and stabilization or increase in BMD in a dose-dependent fashion

5-year, double-blind, randomized study with 1,255 postmenopausal women with established osteoporosis showed a 36% reduction in relative risk of new vertebral fracture among those taking 200 IU qd.

Typical dose 200 IU intranasal alternating nostrils daily. Administer with adequate Ca and Vit D.

Please also see Osteoporosis-Part I by Allan Rubin

FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "How to Select a Nursing Home"

Dr. Susan Rubin
Updated September 9, 2001

http://www.therubins.com

e-mail : hrubin12@nyc.rr.com or rubin@brainlink.com

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