Osteoporosis

Clinical cases and literature review

Catherine Bakewell, MD

Quick overview

Definition(per WHO) normal bone density is a

value within one standard deviation of the mean
value in young adults of the same sex and race.
BMD btw 1 and 2.5 standard deviations below the
mean is defined as osteopenia,
BMD > or = 2.5 standard deviations below the
mean is defined as osteoporosis (and is associated
with skeletal fragility)

Risk Factors

History of fragility fracture in a first-degree relative

Low body weight (less than 58 kg [127 lb])
Current cigarette smoking
Female sex
Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy,
prolonged premenopausal amenorrhea [greater than one year])
White race
Advanced age
Lifelong low calcium intake
Alcoholism
Inadequate physical activity
Recurrent falls
Dementia
Impaired eyesight despite adequate correction
Poor health/frailty
Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism,
hypogonadism, multiple myeloma, celiac disease
Glucocorticoid therapy for more than three months
Other drugs: anticonvulsants, GnRH agonists, lithium, excessive doses of thyroid hormone

Screening
BMD should be measured in all
postmenopausal women < 65 y.o. who have
one or more risk factors for osteoporosis.
Measurement of BMD is also recommended
for all women 65 years and older.

Mrs. T
A 53 year old woman presents to your clinic
with concerns about osteoporosis, and she is
requesting screening.
What do you want to know?

Mrs T. (cont)
You decide to get a DXA scan, which
shows:
A total T score of 2.0 at the hip, and 1.7
at the spine.
She complains of some height loss, but a
chest X-ray is negative for compression
fractures.

Treatment of Osteopenia
You tell her she should take calcium and
vitamin D supplementation.
She asks didnt they just do a study that
showed that that didnt work? I thought I
read something about that in the paper.

EBM

Jackson et al, N Engl J Med. 2006.

Calcium plus Vitamin D supplementation
and the risk of fractures.

Design: Randomized, placebo-controlled trial, 36K women at 40 different sites, healthy, postmenopausal aged 50 70
years (of note, corticosteriod use was an exclusion criteria). Mean follow up period: 7 years.
Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates, and
calcitonin was allowed. 52% of women were taking HT at baseline.
Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, Calcium plus vitamin D did
increase BMD by 0.9% at the hip but not at the spine.
Conclusions: No significant benefit, slight increase in risk of kidney stones

Problems? Flaws?

Study limitations

Although not statistically significant, treated women did have 12% fewer hip fractures,
the type of fracture associated with the largest morbidity and mortality. Plus bone
density at the hip increased slightly.

Women in this trial were also at low risk; many had already had the benefits of taking
large amounts of calcium and vitamin D, and more than half were taking hormone
therapy.

Vitamin D dosing was potentially inadequate (further discussion to follow)

40% of women in the intervention group did not take the supplements

What doses do you recommend?

Vitamin D
Bishoff-Ferrari et al. performed metaanalysis (JAMA 2005)
12 studies included: examined efficacy of
different doses of Vitamin D
Conlusion: oral Vit D btw 700-800 IU/d
reduces risk of non-vertebral fractures; 400
IU/d is not sufficient.

Calcium
To maintain neutral calcium balance:
1,000mg/d for premenopausal women
1,500 mg/d for postmenopausal women

Counselling

Mrs. T needs to be counselled re:

Bisphosphonates for Osteopenia

Should Mrs. T be started on Fosamax?

Physiologic effects

* Decreased bone resorption

* Decreased bone formation by 70-95%

* Increased mineralization density
* Slight increase in bone volume
* Increase bone strength first 5 years
* Decreased fracture rate first 5 years,
compared to placebo
* Half-life in bone greater than 10 years
* Long-term effects on bone unknown

Guidelines

National Osteoporosis Foundation

recommends tx for women with T < -2.0 or
< -1.5 with risk factors.

Schousboe et al, 2005

Modeled cost-effectiveness of treating
osteopenic women with alendronate for 5
years.
Compared cost per quality-adjusted lifeyear (QALY) of tx vs not tx women aged 55
- 75, femoral neck scores of 1.5 to 2.4.
Costs ranged from 74 K to 322K per QALY
gained.

Conclusions
Therapy only deemed cost effective in
women who had risk factors unrelated to
BMD, such as dementia, visual impairment,
or frequent falls.
Current recommendation is to reserve
bisphosphonates for women with T scores of
2.5, or those with osteopenia and
pathologic fracture.

Mrs T. Goes Home

So you decide that Mrs. T should start with

supplementation and lifestyle modification,
and undergo repeat DEXA scan in 2 years
time.

What about other therapies?

Calcitonin
SERMs
Estrogen
Intermittant PTH

Calcitonin
produced by cells in the thyroid gland
acts directly on osteoclasts to stop bone
resorption
Taken as a nasal spray (Miacalcin), dose
200 units per spray (per day)
More expensive than bisphosphonate
Very safe, moderately effective

Estrogen
Reasonable to start under age 60 (or for first
ten post-menopausal years).
Most physicians only recommend for
treatment of post menopausal symptoms.
Excellent at maintaining bone mineral
density.
Consider switching to SERM after 5 10
years.

Selective Estrogen Receptor

Modulators (ex:Raloxifene)
Prevents vertebral osteoporotic fractures in
women with osteoporosis, and stabilizes
bone density.
Physiological substitute for estrogen at the
bone.
Increased risk of thrombosis.
Can worsen menopausal symptoms .

Ms. B
Ms B is a 67 yr old woman with a T-score
of 3. You have had her on Ca, Vit D, and
Boniva (due to her awful GERD) for 2
years now. She develops the acute onset of
thoracic back pain, and CXR reveals a new
compression fracture.
What are you going to do?!

Intermittent PTH

Recombinant (1-34) variant FDA approved in 2002,

stimulates both osteoclasts and osteoblasts.
Intermittent spikes of PTH stimulate more bone formation
than resorption.
Administered at a dose of 20 mcg/day SC for 18 to 24
months.
After discontinuation, patients should be treated for the
next two years with an anti-resorping medication;
otherwise the bone density will decrease.
Other doses, durations are being experimented with, but
not officially approved.

Mrs. S
Mrs. S is a 78 year old woman with
osteoporosis (T score 2.6 at the hip by
DEXA 2 years ago) on Fosamax 70 mg
weekly.
She is concerned because she has heard
about reports of dead jaw bone in people on
this medication.
What do you say to her?

Woo et al, Annals, 2006

Systematic review Bisphosphonates and

Osteonecrosis of the Jaws
368 patient cases
Strongly assoc with use of aminobisphosphonates
(IV preparation), for people with malignancy,
related to severe suppression of bone turnover
94% of pts tx with pamidronate or zoledronic acid
or both

Osteonecrosis, cont

85% of affected patients have metatstatic breast

cancer or multiple myeloma. Only 4% have
osteoporosis.
For pts with cancer receiving IV bisphosphonate,
prevalence 6 10%.
In pts on alendronate for osteoporosis, prevalence
unknown.
60% of all cases occur after dental surgery (such as
tooth extraction), the remaining 40% are assoc with
denture or physical trauma.

Osteonecrosis, cont

Osteonecrosis, cont

Osteonecrosis, cont

Mrs S.
You can reassure Mrs. S that her chances of
osteonecrosis are very, very low.
However, (for other patients) it is
reasonable to hold off on initation of
bisphosphonate until after necessary dental
procedures.

Ms. W

Ms W is a charming 45 year old woman

with rheumatoid arthritis, who has been on
low dose prednisone (5mg/day) for 10 years
now.

What is her risk of osteoporosis?

Glucocorticoid induced bone loss

Unlike other agents that increase bone loss

(thyroxine, sustained PTH), glucocorticoids
accelerate resorption while inhibiting bone
formation.
Patients beginning on high dose prednisone (mean
21mg/day) lost a mean of 27% of their L-spine in
one year
.
Luckily, the decline in BMD slows thereafter.
(Reid et al, 1990)

Mechanisms for glucocorticoid

induced osteoporosis

General guidelines
Keep duration of therapy as short as
possible
Consider high dose pulse therapy rather
than tx for weeks or months
Dont forget the basics (weight bearing
exercise, smoking cessation, minimize
alcohol)

Screening
Measure baseline BMD if it is anticipated
that a patient will be on glucocorticoids for
> 3 mo.
DEXA repeated yearly if on preventative
therapy.

Supplementation

Adequate Calcium and vitamin D supplementation

appear to largely negate the effects of low dose
(up to 10mg/day) steroid administration. (Buckley et al, 1996;
Saag et al, 1998).

Recommended supplemenation doses that for

postmenopausal women: 1500mg Calcium plus
800IU of Vitamin D.

HRT
For premenopausal women with oligo or
amenorrhea on steroids, the ACR
recommends addition of oral contraceptive.
For men with testosterone deficiency
(decreased libido, fatigue) consider
testosterone supplementation.

Bisphosphonates
Should be initiated on essentially everyone
initiating long-term glucocorticoid therapy
(>5mg/day for >3 months) except those on
HRT (unless pt has fxr on HRT) or
premenopausal women who may become
pregnant.
ACR Recommendations (2001 Update)

What would Schousboe say?

Given the high costs of bisphosphonate for
prevention, perhaps a better strategy would
be:
DEXA at baseline and yearly
Start bisphosphonate tx only if BMD is
abnormal (T score < -1.0).
Alendronate 35mg weekly for prevention,
and 70mg weekly for treatment.

Calcitonin
Consider calcitonin if bisphosphonate
contraindicated or not tolerated.
May also reduce pain from prior fractures.

Thiazides
Measure urinary calcium excretion.
Thiazide diuretics (and salt restriction)
shown to decrease calcium excretion.
Enthusiasm tempered by lack of evidence
that thiazides increase BMD in pts on
corticosteriods.

Ms W.
Should have a DEXA scan at the hip and
lumbar spine.
Should be on Calcium and Vit D.
Add bisphosphonate if T score < -1.0.
Consider addition of thiazide, especially if
hypertensive or she has elevated urinary
calcium excretion.
Evaluate for estrogen deficiency.

References

Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis
of randonized controlled trials. JAMA 2005; 293:2257-64.
Buckley LM, Leib ES, Cartularo KS, et al. Calcium and Vitamin D3 supplementation prevents loss in the spine
secondary to low-dose corticosteroids in patients with rheumatoid arthritis. Ann Intern Med.
Med. 1996; 125: 961.
Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J
Med.
Med. 2006;354:669-83.
Laan, RF, Van Riel, PL, Van de Putte, LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in
patients with rheumatoid arthritis. Ann Intern Med 1993; 119:963
Ott S. Osteoporosis and bone physiology:
physiology: description, diagnosis, treatment, and explanation of underlying physiology.
Retrieved on September 26th, 2006 from University of Washington Web Site: http://courses.washington.edu/bonephys/
Primer on the Rheumatic Diseases.
Diseases. 12th Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596.
Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American
College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;
44:1496.
Reid, IR, Heap, SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy.
Arch Intern Med 1990; 150:2545.
Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced
osteoporosis. N Engl J Med.
Med. 1998; 339: 292.
Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal
women. Ann Intern Med.
Med. 2005;142: 734 41.
Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Ann Intern
Med.
Med. 2006;144:753-761.