Metabolic Bone Disease

Ovid: Turek’s Orthopaedics: Principles and Their Application

Editors: Weinstein, Stuart L.; Buckwalter, Joseph A.
Title: Turek’s Orthopaedics: Principles and Their Application, 6th Edition
> Table of Contents > II – General Disorders of the Musculoskeletal System > 7 – Metabolic Bone Disease

Metabolic Bone Disease
Julie T. Lin
Joseph M. Lane
Bone is a living organ that is made primarily of type I
collagen. It provides structural and mechanical support and plays a
central role in mineral homeostasis. Its roles include protecting vital
organs and housing bone marrow—as a site for muscle attachments and as
the primary reservoir for calcium and phosphate.
Bone is comprised of cells and extracellular matrices.
It is a dynamic entity regulated by osteoblasts, which are responsible
for bone formation, and osteoclasts, which are responsible for bone
resorption. Pluripotent mesenchymal cells give rise to marrow
stromal-cell progenitors that can proliferate and differentiate into
osteoblasts. Peak bone mass is established between 20 and 30 years of
age. Multiple factors influence peak bone mass including race,
genetics, nutrition, exercise, and in women, regular menstrual cycles.
Bone strength is related to bone mass, distribution of the mass,
microarchitectural structure, and quality of the bone.


Poor nutritional states such as anorexia nervosa,
especially prevalent in adolescents, disrupt the
hypothalamic-pituitary-gonadal axis, resulting in disturbance of
menstrual cycles. Eating disorders such as anorexia nervosa are
increasingly prevalent, with prevalence rates estimated at 0.5 to 1%
among adolescents and young adults. Certain variables may identify
those patients with anorexia nervosa at highest risk for low bone
density. Lean body mass and low body mass index have been strongly
correlated with amenorrhea and may be even more important than
variables such as participation in physical exercise. Length of
amenorrhea in patients with anorexia nervosa has been inversely
correlated with bone density in the lumbar spine and hip. Additional
important variables include greater than 12 months since onset of
weight loss, calcium intake less than 600 mg/day, and body mass index
less than 15. Regional bone loss may be predicted on the basis of low
body weight.
Prevention of osteoporosis during adolescence in all
patients includes a combination of adequate calcium intake and
exercise, which together may represent the most significant factors.
Adolescent women are at particularly high risk of poor nutrition and
limited caloric intake. One study showed that half of adolescent
females skipped one meal per day, more than half were trying to lose
weight, and almost three-fourths were trying to keep from gaining
The female athlete triad of disordered eating,
amenorrhea, and osteoporosis, also commonly seen in adolescents,
represents a complex interplay of poor nutrition and disrupted
menstrual cycles leading to osteopenia and osteoporosis. This triad may
be particularly prevalent in sports that place high emphasis on
appearance, such as gymnastics and figure skating. Additional
nutritional conditions contributing to osteoporosis include alcoholism,
especially in men. Low bone density in alcoholics appears to be
multifactorial in origin, with hormonal factors, malabsorption, and
liver disease all possible contributors.
Poor intake of calcium, vitamin D, and total protein
directly impact bone density. Poor nutritional states such as protein
and calorie malnutrition stimulate bone resorption and impair bone
formation secondary to reduced serum insulin-like growth factor-I.
Gastrointestinal disorders such as malabsorption syndromes secondary to
celiac sprue, ulcerative colitis, and Crohn’s disease; primary biliary
cirrhosis; chronic obstructive jaundice; and hepatitis are associated
with bone loss. Specifically, the cytokines that are involved in
inflammatory bowel disease and possibly celiac sprue stimulate bone
Menstrual Cycles
Regular menstrual cycles in women are exceedingly
important for bone health. Hypoestrogenism is a well recognized cause
of osteoporosis. In young women, the early diagnosis of primary
amenorrhea is of paramount importance because it strongly correlates
with osteopenia. Eating disorders, hyperandrogenism, and
exercise-induced amenorrhea are all associated with amenorrhea and
The regulation of menstrual cycles is extremely
important and oral contraceptive pills are usually utilized to regulate
cycles. The composition of the pills appears to be an important factor;
it has been suggested that the use of the progestin-only contraceptive
pills, as well as the depot medroxyprogesterone acetate may have
deleterious effects on bone accretion. Therefore, special care may need
to be taken when prescribing oral contraception for the regulation of
menstrual cycles.
Hypoestrogenism in women and low testosterone levels in
men are associated with low bone density. Men who receive treatments
for conditions like prostate cancer with luteinizing hormone-releasing
hormone (LHRH) agonist analogues are at increased risk for low bone
density. The sex steroids are important in men, both during peak bone
formation as well as for the maintenance of bone strength in adults.
Calcium and Vitamin D
Adequate calcium intake is essential during adolescence
and has been shown to increase bone mineral density. It may be most
beneficial to those adolescent girls who are greater than 2 years after
menarche. Vitamin D deficiency has been correlated with low bone
mineral density in adolescent girls, particularly in the lumbar spine.
In adults, adequate calcium and vitamin D intake remains
a priority, with recommended minimum daily intakes of 1200 mg and 400
IU, respectively.


postmenopausal patients may benefit from higher doses of calcium and
vitamin D. The use of calcium and vitamin D in the elderly can result
in gains in bone mineral density in the spine and hip ranging from 1%
to 3%.

Vitamin D is mainly produced in the skin with the
activation of sunlight. It is photoconverted from 7-dehydrocholesterol
in the skin to cholecalciferol (vitamin D3) by UV radiation from
sunlight and in the diet is supplied as either vitamin D3 or from the
plant sterol ergosterol as vitamin D2 (ergocalciferol). Vitamin D is
hydroxylated at the 25 position in the liver and is then hydroxylated
by the 1 α-hydroxylase enzyme in the kidney to the active metabolite
1,25 (OH) 2D.
Vitamin D is needed to maintain calcium homeostasis as
it increases intestinal absorption of dietary calcium. With low dietary
calcium intake, osteoblasts signal osteoclast precursors to mature and
dissolve the calcium stored in bone. Vitamin D is metabolized in the
liver and then the kidney under parathyroid hormone control to 1,
25-dihydroxyvitamin D. 1, 25-dihydroxyvitamin D receptors are present
in many organs, including the intestine, bone, brain, heart, stomach,
and pancreas.
In the elderly, the most common cause of increased bone
resorption is calcium deficiency. Both calcium and vitamin D deficiency
are very common in the elderly and can be attributed to poor diet, lack
of sunlight, malabsorption syndromes, and various drugs that are
degraded by the liver enzymes. Postmenopausal patients supplemented
with calcium and vitamin D have shown preservation of bone mineral
density and a reduction in osteoporotic fractures. Vitamin D deficiency
appears to be widely underdiagnosed and undertreated. Nonambulatory
elderly housebound adults are at particularly high risk of vitamin D
deficiency. Exposure to sunlight can increase bone mineral density in
elderly osteoporotic patients through elevation of 25-hydroxyvitamin D
levels. Vitamin D is an essential vitamin that helps to regulate serum
calcium. Vitamin D deficiency is associated with poorer function and
increased hip fracture prevalence. Women with vitamin D deficiency can
present with normal levels of calcium, increased serum PTH, and
hypocalciuria. Vitamin D and calcium supplementation are associated
with a decreased risk of hip fractures (< 25%) and are shown to be
cost effective.
Calcium and vitamin D may be ingested in foods naturally
containing these nutrients as well as with foods supplemented with the
nutrients. Calcium occurs naturally in dairy products and broccoli.
Foods fortified with calcium including orange juice and cereals can
help to increase dietary intake of calcium. Vitamin D occurs naturally
in foods such as salmon and mackerel and in fish oils including cod
liver oil. Cereals, bread products, and milk fortified with vitamin D
are good supplemental sources of vitamin D.
Physical activity during childhood and adolescence, the
peak bone forming years, is essential. Peak bone mass accretion during
childhood and adolescence may be as important as bone loss, which
occurs during adulthood. Weight-bearing exercise throughout the life
cycle has been shown to be beneficial and appears to be especially
important in adolescence. In combination with calcium supplementation,
weight-bearing exercise has been shown to increase bone mineral density
in adolescent women. High impact weight-bearing exercises may be
particularly effective in premenarchal girls. In mature women, exercise
will not increase bone mass but will improve the quality of bone and
decrease fracture risk.
Weight bearing is essential, while lack of weight
bearing has deleterious effects on bone mineral density. Prolonged
immobilization, secondary to conditions such as spinal cord injury or
coma, as well as prolonged space flight are known to have deleterious
effects on bone density.
Accumulation of Peak Bone Mass
Peak bone mass is accrued during childhood and
adolescence, with almost half of peak adult bone mass acquired during
adolescence. Failure to achieve peak bone mass can contribute to
osteopenia and osteoporosis. Numerous factors contribute to peak bone
mass formation during this time period. These factors include gender,
heredity, nutrition, exercise, and the presence of endocrinopathies.
The role of nutrition, exercise, and presence of endocrinopathies is
discussed elsewhere in this chapter.
During the perimenopausal years, bone resorption is
increased and bone loss accelerated. This is more marked in the
trabecular than in cortical


because of the trabecular bone’s greater surface area. In estrogen
deficient states, remodeling increases: more bone is remodeled on its
endosteal surface and within these sites even more bone is lost as more
bone is resorbed while less is replaced, accelerating architectural
delay. The bone loss that occurs during menopause is associated with
increased periosteal apposition, which partially preserves bone
strength. Areas of the skeleton with primarily trabecular bone, such as
the distal forearm and vertebrae, are particularly susceptible to
fracture during this time.

Osteoporosis: Scope of Problem
Osteoporosis is the most common metabolic bone disease
and affects 200 million worldwide and 25 million in the United States.
It is a disease that is often underlooked and undertreated—likely in
part because it is a clinically silent disease until it manifests in
the form of fracture. Osteoporosis has significant physical,
psychosocial, and financial consequences.
Osteoporosis Definition
Osteopenia and osteoporosis are determined on the basis
of bone mineral density readings. Osteoporosis is a condition in which
bone mineral density decreases and the fragility of bone leads to
increased susceptibility to fracture. The World Health Organization has
defined osteopenia as a T-score of -1 to -2.5 standard deviations below
peak bone mass in controls and osteoporosis as a T-score of -2.5
standard deviations or greater below peak bone mass in controls.
Risk Factors for Osteoporosis
Low bone density represents the main risk factor for
osteoporosis. Major primary risk factors include personal history of
fracture as an adult, history of fragility fracture in a first degree
relative, low body weight (less than 127 lbs), and current smoking.
Additional risk factors include Caucasian race, advanced age, female
sex, dementia, estrogen deficiency (early menopause, bilateral
ovariectomy; prolonged premenopausal amenorrhea (> 1 year), low
lifelong calcium intake, alcoholism, impaired eyesight despite
correction, inadequate physical activity, and poor health/frailty.
Numerous medical conditions and medications are associated with low
bone density. These conditions include hyperparathyroidism,
hyperthyroidism, osteomalacia/rickets, malabsorption syndromes,
inflammatory bowel disease, and multiple myeloma. Medications
associated with increased risk include prolonged heparin use,
anticonvulsants, cytotoxic drugs, and tamoxifen.
Bone Mineral Density Testing
Bone mineral density testing may be performed using dual
energy x-ray absorptiometry (DEXA), quantitative CT, or other
modalities, but DEXA is considered the gold standard. DEXA represents
the areal bone density. Sites of measurement are the spine, the hip,
and the wrists. Precision between tests approximates 2%. The National
Osteoporosis Foundation recommends that bone mineral density should be
measured in the following groups of patients:
1. All women 65 years and older regardless of risk factors.
2. All postmenopausal women
under age 65 years with one or more risk factors for osteoporosis
(other than being white, postmenopausal, and female).
3. Postmenopausal women who
are considering therapy for osteoporosis, if bone mineral density
testing would facilitate the decision.
4. Postmenopausal women who present with fractures (to confirm diagnosis and determine disease severity).
Medicare coverage for bone mineral density testing is as follows:
1. Estrogen deficient women at clinical risk for osteoporosis.
2. Individuals with vertebral abnormalities.
3. Individuals receiving, or planning to receive, long-term corticosteroid therapy.
4. Individuals with primary hyperparathy-roidism.
5. Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy.
Fracture Determinants
Osteoporotic fractures typically occur in regions with
large volumes of cancellous bone. The ability of a structure like
cancellous bone to carry loads depends on several factors including
bone quantity or tissue volume, architecture or tissue geometry, and
material or tissue composition.


Falls or applied loads are implicated in the development
of osteoporotic fractures, especially hip fractures. Falls are
exceedingly common in community dwellers and in the nursing home
setting. Hip fractures are most often associated with falls directly
onto the hip. Determinants of fracture risk in the setting of falls
include hard impact surfaces, quantity of soft tissue covering the hip
region, and low bone density. Causes of falls are multifactorial and
include medications, underlying medical conditions such as peripheral
neuropathy, neuromuscular deficits including weakness, decreased visual
acuity, cognitive impairment, and poor general physical health.
Screening for falls risk should include neuromuscular examination,
watching the patient ambulate and perform tandem gait and simple
functional tests, including the get-up-and-go-test and 6-minute walk
test. These simple tests may be performed in the physician’s office or
a physical therapy gym.
In 2003, the Cochrane Review
assessed the effects of 62 trials involving 21,668 people using
interventions designed to reduce falls risk in the elderly. The trials
focused on falls and number of fallers. The review
concluded that interventions likely to be beneficial in reducing falls
included multidisciplinary, multifactorial, health and environmental
risk factor screening; programs of muscle strengthening and balance
retraining; home hazard assessments and modifications professionally
prescribed for older people with a history of falling; withdrawal of
psychotropic medication; cardiac pacing for fallers with
cardioinhibitory carotid sinus hypersensitivity; and a 15-week Tai Chi
group exercise intervention. The authors found that interventions of
unknown effectiveness included nutritional supplementation,
group-delievered interventions, vitamin D supplementation,
pharmacological therapy, cognitive/behavioral interventions alone,
amongst others. The authors concluded that there are interventions that
are likely to reduce falls, but that further studies assessing
prevention of injuries related to falls are needed.
Secondary causes of osteoporosis should be considered in
the differential diagnosis of osteoporosis and ruled out appropriately.
In one review of 1,015 female patients, a secondary cause for
osteoporosis was found in 8.6% of 384 osteoporotic patients. The most
common secondary causes of osteoporosis included thyrotoxicosis and
parathyroid adenoma. Additional conditions to be considered in the
differential diagnosis of osteoporosis should include diseases of the
bone marrow such as multiple myeloma, connective tissue diseases such
as Ehlers-Danlos and osteogenesis imperfecta, other endocrinopathies
such as type I diabetes mellitus, and Paget’s disease. These conditions
are outlined in the following sections.
Bone Marrow Diseases
Multiple Myeloma
Multiple myeloma is the most common primary neoplasm of
the skeleton. In the United States, approximately 12,000 cases of
multiple myeloma are diagnosed each year. Bone pain related to lytic
lesions is the most common presentation of multiple myeloma. Additional
presentations include systemic symptoms including weakness, infections,
fever, or weight loss. Multiple myeloma should be ruled out with the
use of serum and urine immunoelectrophoresis, serum and urine protein
electrophoresis, complete metabolic panel, and complete blood count. In
a review involving 1,027 patients diagnosed with multiple myeloma,
anemia was present in 73% of patients, hypercalcemia in 13% of
patients, and serum creatinine level of 2 mg/dL or more in 19%, β2-microglobulin
level was increased in 75%, serum protein electrophoresis revealed a
localized band in 82% of patients, immunoelectrophoresis or
immunofixation showed a monoclonal protein in 93%, and a monoclonal
light chain was found in the urine in 78%.
Multiple myeloma may have two distinct presenting
subtypes: presenting with bone lesions and a nodular growth pattern and
the other presenting with anemia and infiltrative growth pattern.
Connective Tissue Disorders
Patients with connective tissue disorders including
osteogenesis imperfecta, Ehlers-Danlos, and Marfan syndrome can present
with low bone density. Patients with these disorders have clinical
findings related to collagen defects. Patients with osteogenesis
imperfecta can present with an array of physical findings including
bone fragility, dentinogenesis, scoliosis, blue sclera, and
hyperlaxity; Ehlers-Danlos patients have hypermobile joints and
hyperelastic skin; and patients with Marfan syndrome have disorders of
the musculoskeletal, cardiovascular, and ocular systems.


Primary Hyperparathyroidism
Primary hyperparathyroidism occurs secondary to
parathyroid gland adenoma in 85% of cases. Other causes include
parathyroid gland hyperplasia or glandular adenocarcinoma. Primary
hyperparathyroidism results in disturbances in serum calcium
homeostasis, which are detected by the kidney. In response to primary
hyperparathyroidism, the kidney increases tubular resorption of
calcium, decreases resorption of phosphate and bicarbonate, and
excretes excessive amounts of calcium in the urine.
Optimal localization imaging techniques include 99m
Tc-sestamibi scintigraphy and ultrasonography. This combination helps
to detect nodular goiter. In addition, a 24-hour urinary calcium
excretion should be obtained in order to rule out familial
hypocalciuric hypercalcemia.
Familial forms of hyperparathyroidism associated with
MEN syndromes including MEN I and MEN II. MEN I is associated with
hyperplasia of the parathyroid gland, with islet cell tumor and
pituitary adenoma. MEN IIa is associated with medullary thyroid
carcinoma with bilateral pheochromocytoma and hyperplasia of the
parathyroid gland and MEN IIb has these findings with neurocutaneous
manifestations without primary hyperparathyroidism.
In primary hyperparathyroidism serum levels of calcium
are elevated and serum levels of phosphate are decreased. Patients
present with weakness, urolithiasis, peptic ulcer disease,
pancreatitis, and bone and joint pain and tenderness. In primary
hyperparathyroidism, the excessive secretion of parathyroid hormone
results in different effects in cortical and trabecular bone. In
cortical bone, bone turnover increases, resulting in increased
resorption at the endosteal envelope, increased cortical porosity, and
thinned cortical bone. This condition is contrasted to cancellous bone,
where there is reduced osteoclastic resorption and osteoblastic bone
formation at individual bone multicellular units, resulting in
diminished erosion depth, decreased bone formation, and decreased
thickness of bone structural units.
Patients with mild primary hyperparathyroidism can be
treated with bisphosphonates at doses similar to those administered in
osteoporosis. In addition, surgical treatment has been very successful
in situations where medical management is insufficient.
Secondary Hyperparathyroidism
Hypocalcemia stimulates parathyroid hormone secretion
and chronic conditions stimulate parathyroid gland hyperplasia
resulting from end-organ resistance to parathyroid hormone. This can be
caused by several different mechanisms including intestinal causes,
impaired PTH action, and loss of calcium from the extracellular
compartment. It is most commonly caused by renal disease.
Intestinal causes of secondary hyperparathyroidism
include impaired dietary calcium intake, impaired dietary calcium
absorption, and vitamin D-deficient states. Impaired PTH action can
result in renal failure, in impaired gut calcium absorption, impaired
parathyroid calcium sensing, and in pseudohypoparathyroidism. Loss of
calcium from the extracellular compartment can occur during bone
growth, during recovery postlactation, in association with
bisphosphonate treatment, during lactation, in cases of idiopathic
hypercalciuria, in increased sodium excretion, with the use of loop
diuretics, and in rhabdomyolysis and sepsis. Nutritional disorders,
with resulting reduced calcium and vitamin D, can also cause secondary
Secondary hyperparathyroidism is commonly caused by
chronic kidney disease which can lead to significant bone loss. It
stems from disruptions in calcium, phosphorus, vitamin D, and
parathyroid hormone metabolism. Early treatment for renal failure
should include restricting dietary levels of protein and phosphorus as
well as supplementation of calcium levels. In secondary
hyperparathyroidism, bone is removed from a dwindling bone mass, with
concurrent bone formation on the periosteal bone surface during aging
that in part offsets bone loss and increases bone’s cross sectional
Treatment of secondary hyperparathyroidism in end stage
renal patients is critical. Important medications in these patients
include noncalcemic vitamin D analogs including 22-oxacalcitriol
(Maxacalcitriol), 19-nor-1a, 25(OH)2D2 (Paracalcitriol), and 1a (OH)2D2
(Doxercalciferol) and calcimimetic agents that bind parathyroid calcium
sensing receptors and reduce PTH secretion.
Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism that occurs in situations
of long-standing secondary hyperparathyroidism is a condition in which
the cause for secondary hyperparathyroidism has been corrected


but the parathyroid glands function autonomously producing hormone despite a lack of calcium imbalance hormone synthesis.

Radiologic findings in hyperparathyroidism include
demineralized and poorly defined bone and the presence of brown tumors.
Rugger jersey spine describes ill-defined bands of increased bone
density next to the vertebral endplates that can occur in any situation
associated with hyperparathyroidism. A bone scan demonstrates
generalized uptake in the skeleton with diminished soft-tissue
activity, giving the “super scan” appearance. Uptake also may be
increased in the long bones, periarticular regions, calvarium,
mandible, a “tie” sternum, and “beading” of the costochondral junctions.
Diabetes Type I
Postteenage women with type I diabetes mellitus have
lower bone mineral density than controls, and are at increased risk of
osteoporosis. Diagnosis is made on the basis of elevated glucose levels.
Cushing’s Syndrome
Cushing’s syndrome, in which there is excessive
endogenous glucocorticoid production, is associated with both
osteopenia and osteoporosis. Diagnosis is made by measurement of
urinary-free cortisol, with surgical treatment the preferred method of
treatment. Iatrogenic Cushing’s disease is common and occurs after
treatment for asthma and polymyalgia rheumatica.
Thyroid hormone suppresses bone formation and patients
with hyperthyroidism are noted to have low bone density. Thyroid
hormone increases osteoclast activity to a greater extent than
osteoblastic activity. Patients with thyrotoxicosis have increased
fracture risk. Surface area of unmineralized matrices increase, with
increased numbers of osteoclasts and resorption sites. Obese patients
often use thyroid overdosage to control their weight.
Rickets and Osteomalacia
Vitamin D deficiency can result in rickets and
osteomalacia in childhood and adulthood, respectively. Rickets is a
disease in growing children or adolescents, and is characterized by
failure or delayed mineralization of endochondral new bone at the
growth plates. Osteomalacia is a failure of mineralization of newly
formed osteoid at sites of bone turnover or periosteal or endosteal
apposition in adults.
Cases of rickets and osteomalacia include lack of
dietary absorption and diminished gut absorption of vitamin D or of
calcium. This may be found in malabsorption syndromes such as Crohn’s
disease or small bowel resection and liver (biliary and hepatocellular)
diseases that lead to problems with gut absorption of vitamin D and
interference with 25-hydroxylation of vitamin D, respectively.
Rickets can be seen in patients with hereditary defects
in vitamin D-signaling molecules, in disorders of phosphate metabolism,
and in situations where there is extrarenal synthesis of
1,25-Hydroxyvitamin D such as in granulomatous disease. Renal diseases
can interfere with 1-hydroxylation of 25-vitamin D. Renal tubular
disorders (vitamin D-resistant rickets), such as x-linked
hypophosphatemia and cystinosis, result in abnormally increased
clearance of inorganic phosphorus (hypophosphatemia) with diminished
ability to mineralize osteoid. Medications such as Dilantin and
phenobarbital can interfere with vitamin D hydroxylation and function.
Clinical findings in patients with rickets and
osteomalacia include painful limbs and muscle weakness, particularly in
the elderly. Common laboratory abnormalities include low normal
calcium, low phosphate, increased intact PTH, increased bone and total
alkaline phosphatase, and low urinary calcium.
Irregular trabeculae may be visualized on radiologic imaging in both rickets and osteomalacia.
In rickets, there is undermineralization of osteoid at
growth plates (metabolically active sites), particularly noted at sites
of rapid bone growth such as proximal and distal femur, proximal tibia,
proximal humerus, and distal radius. Therefore, findings include
widened and irregularly shaped physeal lucencies, many times with
flaring of metaphyses and rachitic rosary in ribs secondary to
involvement at multiple costochondral junctions. Radiographic findings
in osteomalacia include lucent, coarsened bones, due to a mixture of
decreased bone density, and possibly radiographic density contributed
by nonmineralized osteoid. Looser zones or pseudofracture, which are
linear foci of undermineralized osteoid at sites of mechanical loading,
are classically present, and often appear as linear lucencies
perpendicularly oriented to the cortex of the bone with incomplete
penetration of bony width, which usually occur along concave aspects of
bone. These characteristics are commonly seen in the femoral neck,
pubic rami, posterior part of ribs, and below the lesser femoral


and less frequently in the lateral border of the scapulae, forearm, and
wing of ilium. Bone scan can detect cortical infarctions, which are
precursors to Looser’s zones. Vertebral bodies can have a ground glass

Rickets and osteomalacia are both treated with high doses of vitamin D.
Paget’s Disease of Bone
Paget’s disease of bone is a progressive bone disease in
which there is bone hypertrophy and disorganized bone remodeling. It is
characterized by bone expansion, cortical bone thickening, and
trabecular bone thickening. It is suspected that Paget’s disease has an
underlying viral cause. Osteoclasts and osteoclast precursors respond
abnormally to 1,25 (OH)2 D3 and RANK ligand. Osteoclasts are activated
with resultant osteolysis, followed by an osteoblastic response until a
new equilibrium is established between bone production and bone lysis.
Histologically, there is a mosaic-like appearance of osteoid secondary
to rapid disordered bone resorption and production.
Clinical presentations of Paget’s disease of the bone
can include pain, osteoarthritis, deformities, unsteady gait, and
hearing impairments. The three stages of Paget’s disease include (1)
lytic phase; (2) mixed lytic and blastic phase, which corresponds to
onset of osteoblastic activation in response to osteoclastic bone
resorption; and (3) sclerotic phase.
Laboratory values include normal serum phosphorus and
calcium levels but elevated serum alkaline phosphatase, serum, and
urine hydroxyproline. Radiographic imaging and bone scans are useful
diagnostic imaging tools. Radiologic findings of Paget’s disease
include “osteoporosis circumscripta,” which is acutely marginated bone
demineralization during the lytic phase of disease in the skull, and
the “blade of grass and flame-shaped margin,” which describes acutely
marginated demineralization of long bones. In addition, there are
“picture frame vertebrae,” which describes the mixed lytic and
sclerotic phase in the spine, and “cotton wool” skull, which describes
the mixed lytic and sclerotic phase in the skull.
Complications of Paget’s disease include osteoarthritis,
basilar skull invagination, insufficiency fractures, protrusio
acetabuli, and proximal femoral varus deformity. Neurologic
complications related to osseous expansion include sensorineural and
conductional hearing loss and spinal stenosis. Osteosarcoma can rarely
develop in these patients.
Treatment with bisphosphonates is the treatment of
choice, and it addresses osteoclastic-mediated bone resorption.
Calcitonin can also be used for treatment.
Calcium/Vitamin D
Patients with osteoporosis require between 1,200 and
1,500 mg of elemental calcium per day and between 400 and 800 IU of
vitamin D per day. It is essential that calcium and vitamin D are taken
together. Dairy products are a good source of calcium but most
individuals require dietary supplementation with calcium carbonate or
calcium citrate. Vitamin D is found in fish, such as salmon and
mackerel; in fish liver oils, such as cod oil; and in fortified foods,
such as orange juice and cereals.
Bisphosphonates represent the most potent class of drug
in the prevention and treatment of osteoporosis. This class of drugs
are pyrophosphate analogs, which strongly bind to the hydroxyapatite of
bone, inhibiting osteoclast activity. Alendronate (Fosamax) and
risedronate (Actonel) are the two main oral bisphosphonates utilized
for osteoporosis, with the intravenous bisphosphonates pamidronate
(Aredia) and zolendronate (Zometa) used off label. Adverse effects for
the oral bisphosphonates include gastrointestinal complications such as
gastritis or esophagitis, abdominal pain, nausea, vomiting, diarrhea,
and constipation, while adverse effects for the intravenous
bisphosphonates include fevers and a flu-like syndrome. The
administration of concurrent acetaminophen, antihistamine, and
nonsteroidal anti-inflammatory medication helps to minimize these
transient complications.
Alendronate has been proven to be effective in
postmenopausal osteoporosis in increasing bone mineral density and
decreasing the risk of fracture. A 5 mg daily dose of alendronate
administered for 24 months, and then increased to 10 mg, results in
fewer radiographic vertebral fractures in the treatment group versus
placebo, with average increases in the lumbar spine BMD of about 5%
after one year, and then 1.5% per year for the next 2 years. At the end
of 3 years, BMD increases by about 6% in the femoral neck and about 7%
in the trochanter.


has demonstrated efficacy in men and individuals on steroids. A single
weekly dose is as clinically effective as daily dosages. Alendronate
decreases spinal and appendicular fractures by 50%.

Risedronate has also been shown to be effective in
increasing BMD and in reducing fracture risk. Treatment with a 5 mg
daily dose of risedronate reduces the risk of new vertebral fractures
by 62% versus control and reduces new vertebral fractures by 90% versus
control. A 5 mg oral daily dose of risedronate results in BMD increases
after only 6 months of therapy, and at 24 months, lumbar spine BMD is
increased from baseline by 4%, with increases of 1.3% and 2.7% seen in
the femoral neck and femoral trochanter, respectively. A 35 mg once
weekly dose of risedronate appears to be as effective as a 5 mg daily
dose in reducing vertebral fracture risk. Like alendronate, risedronate
also decreases hip fractures.
Parenteral pamidronate has also been used off label in
the treatment of postmenopausal women with osteoporosis who are
intolerant to oral bisphosphonates. It has been shown to be have
comparable effects on bone mineral density when compared with
alendronate. Fracture data are currently not available.
Parenteral zolendronate, also used off label,
administered at intervals of one year, produced comparable effects on
bone turnover and BMD to those seen with oral dosing with
bisphosphonates. A randomized, double-blind, placebo-controlled trial
documented bone mineral density increases in the treatment group that
were 4.3 to 5.1% higher than those in the placebo group, with
suppressed biochemical markers of bone formation.
Parathyroid Hormone
Parathyroid hormone is the anabolic agent approved for
the treatment of osteoporosis. Approved by the U.S. Food and Drug
Administration in November 2002, this subcutaneous daily medication has
shown promising results in prospective studies.
The 20-mcg dose of 1-34 parathyroid hormone has been
shown to both increase bone mineral density and decrease fracture risk,
with fewer side effects than the 40-microgram dose. In a study
involving 1,637 postmenopausal women with prior vertebral fractures,
women who took a 20-mcg daily dose of 1-34 parathyroid hormone
demonstrated a 0.35 relative risk of fracture compared to placebo and
increases of 9% in the lumbar spine and 3% in the femoral neck.
The use of parathyroid hormone in the treatment
logarithm of osteoporotic patients remains unclear. Clinical studies
have suggested that the concomitant administration of parathyroid
hormone with bisphosphonate medication may mitigate parathyroid
hormone’s effects. In a study involving 83 men with low bone density
randomized to received alendronate, parathyroid hormone, or both, bone
density in the lumbar spine and femoral neck increased significantly
than in the other groups (p < 0.001). The combination therapy group
had increased bone density in the lumbar spine and femoral neck
compared to those in the alendronate group. Another study involving 238
postmenopausal women using 100 mg of daily parathyroid hormone (1-84),
alendronate or both showed that the volumetric density of the
trabecular bone at the spine in the parathyroid hormone group increased
about twice that in either of the other groups after 12 months.
Nasal calcitonin (Miacalcin) is helpful in the
management of bony pain secondary to fracture and also works to
increase bone mineral density and decrease fracture risk. Typically,
analgesia for bone pain is achieved as early as the first to second
week of use. The mechanism of activity is not well understood, though
the endogenous opiate system may play a role in mediating the analgesic
effects. A 5-year, double-blind, randomized, placebo-controlled study
in 1,255 women with established osteoporosis demonstrated that the 200
IU dose reduces the risk of new vertebral factures by 33% compared to
placebo, with gains of 1 to 1.5% in the lumbar spine bone mineral
density in patients receiving 100, 200, and 400 IU of calcitonin daily.
It has no protective action regarding hip fractures.
Estrogen/Selective Estrogen Receptor Modulators
Estrogen used for the alleviation of symptoms following
menopause may increase bone density and decreases fractures by 35%, but
is not used as a primary agent in the treatment of osteoporosis due to
its many potential complications. Estrogen has been associated with
increased incidence of coronary heart disease events, strokes,
pulmonary embolisms, and invasive breast cancers in patients receiving
conjugated equine estrogens plus progestin. Therefore, it has been
concluded that the overall health risks from estrogen exceeds the
benefits from use.


Selective estrogen receptor modulators such as
raloxifene may increase bone mineral but are not considered primary
agents in the treatment of osteoporosis. They decrease spine fracture
by 35 to 40% but have no effect on hip fractures. Furthermore, they
have been associated with venous thromboembolism and hot flashes.
Nonmedical Management of Osteoporosis
The nonmedical treatment of osteoporosis represents an
extremely important, though often overlooked, facet of the appropriate
management of osteoporotic individuals. Treatments, including physical
therapy, the use of orthoses such as the posture training support and
hip protectors, and the minimally invasive spine procedures
vertebroplasty and kyphoplasty, are exceedingly important players in a
comprehensive multidisciplinary management approach to osteoporosis.
Physical therapy and exercise programs should be
specifically geared toward the patient with osteoporosis. Balance
exercises and strengthening exercises of the bilateral lower
extremities and weight-bearing exercises may help to decrease fall
risks. In particular, Tai Chi has been shown to reduce falls risk
almost by 50%. Back extensor strengthening exercises can decrease
thoracic kyphosis and possibly prevent vertebral compression fractures.
In addition, aerobics and weight-bearing and resistance exercises can
increase bone mineral density in the spine, and walking can result in
increased bone mineral density in the hip.
Hip protectors are orthoses comprised of padding placed
in undergarments worn over the greater trochanter to help absorb impact
on fall. They have been documented to significantly decrease hip
fracture risk in elderly institutionalized patients. Poor patient
compliance remains the main obstacle to their use. The posture training
support, CASH (cruciform anterior spinal hyperextension) brace, and the
Jewett brace can all be used in individuals with symptomatic vertebral
compression fractures to minimize thoracolumbar flexion. The posture
training support may minimize the symptoms accompanying painful
vertebral compression fractures.
Vertebroplasty and kyphoplasty are two minimally
invasive spine procedures utilized in the management of painful
vertebral compression fractures that have demonstrated excellent
results in alleviation of pain. Both procedures involve placement of
polymethylmethacylate into a symptomatic fractured vertebral body.
Kyphoplasty provides excellent reduction of fracture, restoring
vertebral body height and restoring function.
Bone is a dynamic organ that has many functions. Many
factors, including nutritional status, hormonal status, calcium and
vitamin D, and regular weight-bearing exercise, play a role in bone
Osteoporosis is a condition with decreased bone mineral
density and resulting increased fragility. It is the most common
metabolic bone disease but is often underdiagnosed and undertreated.
Osteoporosis can be treated with medical management as well as a
comprehensive multidisciplinary approach.
The differential diagnosis for osteoporosis includes
other metabolic bone diseases, including hyperparathyroidism,
rickets/osteomalacia, and Paget’s disease, among others. These
conditions should be ruled out appropriately.
Annotated Bibliography
Bone Growth/Development
F, Brazier M, Kamel S et al. Effects on bone mineral density of calcium
and vitamin D supplementation in elderly women with vitamin D
deficiency. Joint Bone Spine 2003;70(3):203-208. In
this placebo-controlled, double-blind randomized study, elderly vitamin
D-deficient women (defined as serum 25(OH)D ≤12ng/ml) in the study
group were given calcium carbonate and vitamin D. Compared to controls,
women in the study group had significantly improved bone mineral
density in the lumbar spine, femur, trochanter, and whole body after 1
Calcium supplementation on bone loss in postmenopausal women. Cochrane Database Syst Rev 2003;4:CD004526. This
review of 15 trials involving 1,806 participants found efficacy for
calcium after 2 or more years of treatment on bone mineral density.
Percentage increases range from 1.6% in the hip to 2.05% for the total
body. Relative risk for fracture was 0.79 and 0.86 for the vertebrae
and nonvertebral fractures, respectively.
G, Giorgino R, Rini GB et al. Prevalence of hypovitaminosis D in
elderly women in Italy: clinical consequences and risk factors.
Osteoporos Int 2003;14(7):577-582. This
multicenter study involving 700 elderly Italian women identified
vitamin D deficiency in 76% of women, with severe vitamin D deficiency
in 27% of women. Hypovitaminosis D was associated with diminished
ability to perform activities of daily living and higher hip fracture


A, Sievanen H, Kannus P et al. High-impact exercise and bones of
growing girls: a 9-month controlled trial. Osteoporos Int
2000;11(12):1010-1017. This study involving 64 pre- and postmenarchal girls participating in a supervised 9-month step aerobic program found that more significant gains in bone mineral acquisition could be achieved before menarche than following menarche.
D, Willett W, Colditz G. Walking and leisure-time activity and risk of
hip fracture in postmenopausal women. JAMA 2002;288(18):2300-2306. This
study involving 61,200 postmenopausal nurses found that moderate levels
of exercise, such as walking, are correlated with lower risks of hip
fracture. For each increase of 3 metabolic equivalent hours per week of
activity, risk of hip fracture was lowered by 6%.
Seeman E. Invited review: pathogenesis of osteoporosis. J Appl Physiol 2003; 95(5):2142-2151. This is a good review of the abnormal bone modeling and remodeling that takes place in osteoporosis.
Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement 2000;17(1):1-45. Summarizes
the conclusions and recommendations of the NIH Consensus Development
Conference on Osteoporosis Prevention, Diagnosis, and Therapy.
van der Meulen MC, Jepsen KJ, Mikic B. Understanding bone strength: size isn’t everything. Bone 2001;29(2):101-104. This is an excellent overview of the determinants of bone strength.
SL, Myers ER, Kiel DP et al. Fall direction, bone mineral density, and
function: risk factors for hip fracture in frail nursing home elderly.
Am J Med 1998;104(6):539-545. In this
prospective, case-controlled study, a fall to the side, low hip bone
density, and impairment in mobility were all identified as independent
risk factors for hip fracture in frail, elderly nursing home fallers.
Tinetti ME. Clinical practice. Preventing falls in elderly persons. N Engl J Med 2003; 348(1):42-49. This
is a good review of fall management in the elderly, particularly useful
for primary care physicians and other physicians caring for the elderly.
L, Gillespie W, Robertson M et al. Interventions for preventing falls
in elderly people. Cochrane Database Syst Rev 2003; 4:CD000340. This
is a comprehensive meta-analysis of the various interventions for
preventing falls. This review included 62 trials with 21,668
participants. Effective measures include multidisciplinary health and
environment risk factor screening and intervention programs, muscle
strengthening and muscle retraining programs, home hazard assessment
and modification, withdrawal of psychotropic medication, cardiac
pacing, and Tai Chi.
Differential Diagnosis of Osteoporosis
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343(25):1863-1875. This is a good review of hyperparathyroidism.
Treatment of Osteoporosis
Lin JT, Lane JM. Bisphosphonates. J Am Acad Orthop Surg 2003; 11(1):1-4. This
is a review of the current knowledge of the oral and intravenous
bisphosphonate medications in various metabolic bone disorders relevant
to orthopedists.
DM, Cummings SR, Karpf DB et al. Randomised trial of effect of
alendronate on risk of fracture in women with existing vertebral
fractures. Fracture Intervention Trial Research Group. Lancet 1996;
348(9041):1535-1541. This study involved 2,027
women in the Fracture Intervention Trial, whose goal was to assess the
effect of alendronate on the risk for morphometric and clincically
evident fractures in postmenopausal women with low bone mass. The study
concluded that women who received alendronate for 36 months had reduced
frequency of morphometric and clinically apparent vertebral fracture
compared to controls.
S, Cepollaro C, Montagnani A et al. Alendronate treatment in men with
primary osteoporosis: a three-year longitudinal study. Calcif Tissue
Int 2003; 73(2):133-139. In this study involving
77 osteoporotic men, subjects who received alendronate plus calcium
compared to calcium alone demonstrated significant improvements in bone
mineral density.
MM, Gilchrist N, Bone HG et al. Therapeutic equivalence of alendronate
35 milligrams once weekly and 5 milligrams daily in the prevention of
postmenopausal osteoporosis. Obstet Gynecol 2003;101(4):711-721. This
1-year, double-blind study of postmenopausal women found that
alendronate 35 mg weekly is therapeutically equivalent to alendronate 5
mg daily. Weekly alendronate is associated with greater dosing
convenience and good tolerability.
NB, Josse RG, Hamdy RC et al. Risedronate prevents new vertebral
fractures in postmenopausal women at high risk. J Clin Endocrinol Metab
2003;88(2):542-549. This study combined data form
two randomized, double-blind studies and found that significant
fracture risk is noted 1 year after treatment. There was a risk
reduction of new vertebral fractures by 62% and reduction of multiple
new vertebral fractures by 90%, compared to controls.
I, Ribot C, Smith R et al. Risedronate reverses bone loss in
postmenopausal women with low bone mass: results from a multinational,
double-blind, placebo-controlled trial. BMD-MN Study Group. J Clin
Endocrinol Metab 2000; 85(5):1895-1900. This
study found that postmenopausal women with low bone mass who received
risedronate 5 mg daily demonstrated increases in bone mineral density
as early as 6 months following treatment and had upper gastrointestinal
adverse events that were similar to placebo.
NB, Lindsay R, Li Z et al. Use of matched historical controls to
evaluate the anti-fracture efficacy of once-a-week risedronate.
Osteoporos Int 2003; 14(5):437-441. Using matched
historical control data from previous placebo-controlled trials, the
authors found that risedronate 35 mg weekly appears to have similar
efficacy to risedronate 5 mg daily in reducing the risk of new
vertebral fractures in the first year of treatment.
AC, Juttmann JR, Wolffenbuttel BH. Intravenous pamidronate compared
with oral alendronate for the treatment of postmenopausal osteoporosis.
Neth J Med 2002; 60(8):315-319. This
retrospective study compared the efficacy of intravenously administered
pamidronate with oral alendronate and found that monthly intravenous
pamidronate is at least as good as oral alendronate in improving bone
mineral density in women with postmenopausal osteoporosis.
IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in
postmenopausal women with low bone mineral density. N Engl J Med
2002;346(9):653-661. In this 1-year, randomized,
double-blind, placebo-controlled trial, the authors found that
intravenous zoledronic acid in postmenopausal women resulted in
increased bone mineral density and suppressed biochemical markers of
bone resorption as great as those achieved with oral daily dosing with
RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1-34)
on fractures and bone mineral density in postmenopausal women with
osteoporosis. N Engl J Med 2001;344(19):1434-1441. This
important randomized trial involving 1,637 postmenopausal women found
that daily injections of parathyroid hormone in postmenopausal women
with prior vertebral fractures resulted in decreased risk of vertebral
and nonvertebral fractures and increased vertebral, femoral, and
total-body bone mineral density.


DM, Greenspan SL, Ensrud KE et al. The effects of parathyroid hormone
and alendronate alone or in combination in postmenopausal osteoporosis.
N Engl J Med 2003; 349(13): 1207-1215. This
randomized, double-blind trial compared the effects of parathyroid
hormone and alendronate alone or in combination and found that there
was no evidence of synergistic effects of parathyroid hormone and
alendronate. Instead, there was the suggestion that concurrent use of
alendronate may reduce the anabolic effects of parathyroid hormone.
JS, Hayes A, Hunzelman JL. The effects of parathyroid hormone,
alendronate, or both in men with osteoporosis. N Engl J Med
2003;349(13):1216-1226. This randomized trial
involved 83 men with low bone density and compared the effects of
parathyroid hormone, alendronate, or both. The authors found that bone
mineral density increased more in the lumbar spine and femoral neck
than in the alendronate group, and bone mineral density increased more
in the lumbar spine in the combination therapy group than in the
alendronate group. The authors concluded that alendronate appears to
limit the effects of parathyroid hormone on bone mineral density in the
lumbar spine and femoral neck in men.
CH III, Silverman S, Andriano K et al. A randomized trial of nasal
spray salmon calcitonin in postmenopausal women with established
osteoporosis: the prevent recurrence of osteoporotic fractures study.
PROOF Study Group. Am J Med 2000;109(4):267-276. This
5-year, randomized, double-blind, placebo-controlled trial involving
1,255 postmenopausal osteoporotic women found that salmon calcitonin
nasal spray resulted in significant risk reductions of new vertebral
JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal results From the
Women’s Health Initiative randomized controlled trial. JAMA
2002;288(3):321-333. This well-known trial
reported the results of the risks and benefits of estrogen plus
progestin in 16,608 healthy postmenopausal women after a mean of 5.2
years and determined that the overall health risks exceeded benefits.
Risks included increased coronary heart disease, stroke, pulmonary
embolus, and breast cancer.
Lin JT, Lane JM. Nonmedical management of osteoporosis. Curr Opin Rheumatol 2002;14(4):441-446. This
is a review of the nonmedical management of osteoporosis, including
strengthening and weight-bearing exercise, Tai Chi, bracing, and hip
SL, Barnhart HX, Kutner NG et al. Reducing frailty and falls in older
persons: an investigation of Tai Chi and computerized balance training.
Atlanta FICSIT Group. Frailty and injuries: cooperative studies of
intervention techniques. J Am Geriatr Soc 1996;44(5):489-497. This
prospective, randomized, controlled clinical trial involving 200
elderly participants with an intervention length of 15 weeks, found
that Tai Chi can reduce the risk of multiple falls by 47.5%.
D, Shea B, Iovine R et al. Exercise for preventing and treating
osteoporosis in postmenopausal women. Cochrane Database Syst Rev
2002;(2):CD000333. This meta-analysis included 18
randomized, controlled trials involving exercise for preventing and
treating osteoporosis in elderly women and found that aerobic,
weight-bearing, and resistance exercises all had positive effects on
bone mineral density of the spine. However, the authors criticized the
studies for having low quality reporting of the trials.
MJ, Gillespie LD, Gillespie WJ. Hip protectors for preventing hip
fractures in the elderly. Cochrane Database Syst Rev 2004;(3):CD001255.
This meta-analysis included 13 randomized trials
involving the use of hip protectors for preventing hip fractures in the
elderly. Data from the cluster randomized studies suggests that hip
protectors reduce the incidence of hip fractures in patients with high
risk of hip fractures living in institutionalized settings.
Deramond H, Mathis JM. Vertebroplasty in osteoporosis. Semin Musculoskelet Radiol 2002;6(3):263-268. This is a good review of the use of vertebroplasty in osteoporotic patients.
JT, Renfro M. Balloon kyphoplasty: one-year outcomes in vertebral body
height restoration, chronic pain, and activity levels. J Neurosurg
Spine 2003;98(1 Suppl):36-42. This retrospective
chart review followed the authors’ first 96 patients with 133 fractures
and reported that kyphoplasty increased vertebral body height,
decreased back pain, and restored function.

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