Clinical cases and literature review
Catherine Bakewell, MD
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)
History of fragility fracture in a first-degree relative
Low body weight (less than 58 kg [127 lb])
Current cigarette smoking
Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy,
prolonged premenopausal amenorrhea [greater than one year])
Lifelong low calcium intake
Inadequate physical activity
Impaired eyesight despite adequate correction
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
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.
A 53 year old woman presents to your clinic
with concerns about osteoporosis, and she is
What do you want to know?
Mrs T. (cont)
You decide to get a DXA scan, which
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
Treatment of Osteopenia
You tell her she should take calcium and
vitamin D supplementation.
She asks ―didn’t they just do a study that
showed that that didn’t work? I thought I
read something about that in the paper.‖
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
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
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?
Bishoff-Ferrari et al. performed meta-
analysis (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.
To maintain neutral calcium balance:
1,000mg/d for premenopausal women
1,500 mg/d for postmenopausal women
Mrs. T needs to be counselled re:
Bisphosphonates for Osteopenia
Should Mrs. T be started on Fosamax?
* 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
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
Compared cost per quality-adjusted life-
year (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
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
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
What about other therapies?
produced by cells in the thyroid gland
acts directly on osteoclasts to stop bone
Taken as a nasal spray (Miacalcin), dose
200 units per spray (per day)
More expensive than bisphosphonate
Very safe, moderately effective
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
Consider switching to SERM after 5 – 10
Selective Estrogen Receptor
Prevents vertebral osteoporotic fractures in
women with osteoporosis, and stabilizes
Physiological substitute for estrogen at the
Increased risk of thrombosis.
Can worsen menopausal symptoms.
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
What are you going to do?!
Recombinant (1-34) variant FDA approved in 2002,
stimulates both osteoclasts and osteoblasts.
Intermittent spikes of PTH stimulate more bone formation
Administered at a dose of 20 mcg/day SC for 18 to 24
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 is a 78 year old woman with
osteoporosis (T score –2.6 at the hip by
DEXA 2 years ago) on Fosamax 70 mg
She is concerned because she has heard
about reports of dead jaw bone in people on
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
85% of affected patients have metatstatic breast
cancer or multiple myeloma. Only 4% have
For pts with cancer receiving IV bisphosphonate,
prevalence 6 – 10%.
In pts on alendronate for osteoporosis, prevalence
60% of all cases occur after dental surgery (such
as tooth extraction), the remaining 40% are assoc
with denture or physical trauma.
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
Ms W is a charming 45 year old woman
with rheumatoid arthritis, who has been on
low dose prednisone (5mg/day) for 10 years
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
Patients beginning on high dose prednisone (mean
21mg/day) lost a mean of 27% of their L-spine in
one year .
(Reid et al, 1990)
Luckily, the decline in BMD slows thereafter.
Mechanisms for glucocorticoid
Keep duration of therapy as short as
Consider high dose pulse therapy rather
than tx for weeks or months
Don’t forget the basics (weight bearing
exercise, smoking cessation, minimize
Measure baseline BMD if it is anticipated
that a patient will be on glucocorticoids for
> 3 mo.
DEXA repeated yearly if on preventative
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.
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
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
ACR Recommendations (2001 Update)
What would Schousboe say?
Given the high costs of bisphosphonate for
prevention, perhaps a better strategy would
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.
Consider calcitonin if bisphosphonate
contraindicated or not tolerated.
May also reduce pain from prior fractures.
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
Should have a DEXA scan at the hip and
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
Evaluate for estrogen deficiency.
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. 1996; 125: 961.
Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J
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: description, diagnosis, treatment, and explanation of underlying physiology.
Retrieved on September 26th, 2006 from University of Washington Web Site:
Primer on the Rheumatic 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;
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. 1998; 339: 292.
Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal
women. Ann Intern Med. 2005;142: 734 – 41.
Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Ann Intern