Metabolic Bone Diseases

By admin On Oct 2, 2024

Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section II – Specific Bone Neoplasms and Simulators > 10 – Metabolic Bone Diseases

Metabolic Bone Diseases

Susan V. Bukata

Metabolic bone diseases include a variety of diseases
that affect the strength and overall quality of bones. Some of these
diseases affect a huge proportion of the population. Osteoporosis alone
affects 45% of women over age 50. Other diseases are extremely rare and
usually result from a genetic anomaly that affects normal bone
metabolism. In every metabolic bone disease there is an imbalance in
the cells and pathways that allow for the skeleton to be continually
remodeled throughout one’s lifetime.

Pathophysiology Fundamentals

Bone metabolism is an integral part of the endocrine system.
Three cell types are involved:
- Osteoblasts
  - Originate from mesenchymal cells
  - Synthesize organic bone matrix
  - Bear receptors for parathyroid hormone and hormones, including estrogen
  - Produce osteoprotegerin (OPG) and receptor activator of nuclear factor (NF)-kappa B (RANK) ligand
  - Produce alkaline phosphatase (marker for bone formation)
- Osteoclasts
  - Originate from monocyte precursors
  - Recruitment/development/activity signals through RANK ligand and macrophage colony-stimulating factor (M-CSF)
  - Resorb bone at ruffled membrane
  - Secrete protons/lysosomal enzymes
- Osteocytes
  - Derived from osteoblasts encased in matrix
  - Interconnected through cytoplasmic processes
  - No longer form bone
  - Respond to mechanical signals and influence remodeling

RANK/RANK-Ligand Signaling

Responsible for the coordination between
osteoblasts and osteoclasts; plays an important role in bone
metabolism. The osteoblast is the cell controlling this pathway.
- RANK-ligand (RANK-L) signal on surface of osteoblasts and secreted by them
- RANK receptor on osteoclast
- OPG is inhibitor of RANK-L (blocks binding to RANK).

Bone Metabolic Unit

Osteoclastic bone resorption and osteoblastic bone formation
Concept of coupling
- Resorption > formation leads to bone loss.
- Resorption < formation leads to bone gain.
- Resorption = formation leaves bone mass balanced.
Peak bone mass reached at age 25 to 30.
After that, resorption is slightly greater than formation, leading to
slow bone mass loss.

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Calcium

Regulation is extremely important in bone mass maintenance.
- Intestines/kidneys/bone involved in calcium metabolism
- Bone first source for calcium when needed (99% of body store is there)
- Active absorption in duodenum (calcium binding protein)
- Passive absorption in jejunum
- Calcium balanced when renal excretion = intestinal absorption
- Renal reabsorption
  - Actively in distal convoluted tubule
  - Passively in proximal tubule and loop of Henle
Dietary intake requirement varies with age.
- Adolescents age 9 to 18 need >1,300 mg daily.
- Age 19 to 49 need >1,000 mg daily.
- Older adults >50 need >1,200 mg daily.
Drugs that decrease calcium retention (thus increase calcium loss)
- Furosemide (Lasix)
- Heparin
- Corticosteroids
- Tetracycline
Drugs that increase calcium retention
- Hydrochlorothiazide (HCTZ): can be used to help retain calcium through renal channels in patients with high urinary loss

Vitamin D

Important for calcium regulation and bone health
- Fat-soluble steroid hormone
- Sources
  - Diet (vitamin D₂)
  - Endogenous production in skin (vitamin D₃)
- Hydroxylated in liver (at 25th carbon), then kidney (at 1st carbon) to create 1,25-dihydroxyvitamin D
- 25-hydroxyvitamin D also recognized as important in maintaining bone health
  - Levels >30 ng/dL desired
- Targets
  - Kidney: increases resorption in proximal tubule
  - Intestines: regulates production of calcium binding protein
  - Bone: major target enhancing mobilization of calcium stores
- Receptors on osteoblasts stimulate RANK ligand production and therefore osteoclast development and activity.
- Recommended daily intake: 400 to 800 IU daily for adults

Parathyroid Hormone

Controls regulation of serum calcium levels
Calcium-sensing receptor on parathyroid cells initiates hormone release with low serum calcium levels.
Bone: PTH binds to osteoblast receptors
- Neutral protease release initiates bone remodeling.
- Stimulates production of factors that signal osteoclasts to resorb bone.
Kidney
- Proximal tubule: PTH decreases PO₄ resorption
- Distal tubule: PTH increases calcium resorption
Stimulates 1α hydroxylase to increase 1,25-vitamin D levels
Intestine
- Increases calcium binding protein production to increase calcium absorption
- Greatest quantitative effect on calcium
PTHrP production by some cancers with similar effects

Osteoporosis

Osteoporosis is a metabolic bone disease characterized
by low bone mass and a microarchitectural deterioration of bone tissue
that results in enhanced bone fragility and a consequent increase in
fracture risk.

Pathophysiology

Imbalance in bone metabolic unit between osteoclastic bone resorption and osteoblastic bone formation
- Resorption > formation leads to bone loss.
Peak bone mass reached at age 25 to 30
After age 30, resorption is slightly greater than formation.
Can see rapid increase in bone resorption during menopause
- Can see 30% bone mass loss over perimenopausal period

Epidemiology

Etiology is unknown.
Affects 45% of women and 25% of men aged 50 and older
Osteoporotic fractures
- 4 times more common than stroke
- Having one is a major risk factor for subsequent fractures.
  - 10% have another fragility fracture in <1 year.
  - 17% to 21% have another fragility fracture in <2 years.
- Pose a lifetime risk of death comparable to breast cancer
1 in 3 women and 1 in 6 men will suffer a hip fracture.
- Annual hip fractures
  - United States: >300,000
  - Europe: >400,000
  - Incidence expected to double over the next 50 years.
Surgeon General’s report in 2004 recognizes poor bone health as an epidemic and major health crisis.
- Personal cost of fracture
- Quality of life
- Economic costs of fracture

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Risk factors for osteoporosis
- Genetic
  - Female > male
  - Caucasian or Asian > Hispanic or African American
- Environmental
  - Smoking
  - Alcohol
  - Sedentary lifestyle
  - Low body weight (<85% ideal body weight or <120 lbs)
  - History of eating disorder
- Other
  - Personal/family history of fragility fracture
  - Age >50

Classification

High-turnover osteoporosis
- Primary form at menopause, but can be seen at any age and in men
- Enhanced osteoclastic bone resorption with more and deeper lacunae
- Osteoblasts unable to fully replace resorbed bone
- Elevated bone turnover markers
- Bone loss rate can be 2% to 3% per year, lasting 6 to 10 years.
Low-turnover osteoporosis
- Most commonly seen with aging, but can be seen at any age
- Failure of osteoblasts to form bone
- Bone formation markers show decreased
  levels (not good bone formers); osteoclastic bone resorption is normal
  or slightly decreased.
- Bone turnover markers at premenopausal level or lower
- Can also be seen in individuals with underlying genetic collagen disorder

Diagnosis

Clinical Features

Biochemical markers
- Collagen cross-link products measured for bone loss rate
  - Urine N-telopeptide
    - Measure in any urine except the first of the day
    - Generally want to have value <30 nM BCE/mM creatinine, definitely <40 nM BCE/mM in postmenopausal women and older men
    - Expect marker level to go down with bisphosphonate treatment by at least 30% to 40% from baseline.
  - Serum cross laps
    - Diurnal variation for each individual
    - More commonly used in Europe
- Markers for bone formation (low levels = poor bone formation)
  - Osteocalcin
  - Alkaline phosphatase
    - Get bone-specific alkaline phosphatase (BSAP), or also need liver function enzymes to evaluate if liver activity is elevated.
- All biochemical markers are elevated in the setting of a healing fracture and then return to baseline.

Radiologic Features

Dual-Energy X-Ray Absorptiometry {lDXA}

Currently gold standard
Low radiation doses (1 to 3 mrem), short scanning times
Error range from 3% to 5% between serial scans on same machine, can be greater between scans on different machines
DXA scan scoring (matching race and gender)
- T-score
  - Compares density relative to peak bone mass (normal healthy 25-year-old)
  - Score used to determine level of disease over age 25
- Z-score
  - Compares density to peers of same age
  - Measurement used for children and adults up to age 25

Quantitative Computed Tomography (CT)

More radiation exposure, more operator-dependent
Assesses both trabecular and cortical areas separately
Use hydroxyapatite phantom for calculating density.

Ultrasound

May be a good tool for preliminary screening
Can evaluate only subcutaneous bones (calcaneus/tibia)
Fracture risk at hip/spine not highly correlated (only 70%)

World Health Organization Definitions of Osteoporosis and Osteopenic

Bone mass measured at hip and spine for adults
- Defined from lower of two levels
- Total body and spine measured for children
1 to 2.4 standard deviations below peak bone mass (T = -1.0 to -2.4)
- Osteopenic with range of mild to moderate bone deficiency
>2.5 standard deviations below peak mass (T = -2.5 or lower)
- Osteoporotic
Fragility fracture defines as osteoporotic regardless of T-score

Diagnostic Work-up Algorithm

DXA scan for bone density
Laboratory tests
- Intact parathyroid hormone (PTH)
- 25-vitamin D level
- 1,25-vitamin D level
- Serum calcium
- Serum alkaline phosphatase
- 24-hour urinary calcium
- Urine N-telopeptide

Treatment

Prevention

Attainment of peak bone mass (age 20 to 30)

Prevention of postmenopausal resorption and agerelated bone loss (Table 10-1)

Table 10-1 Prevention of Postmenopausal Resorption and Age-Related Bone Loss

Treatment	Dose	Side Effects	Issues with Treatment	Mechanism of Action
Oral Bisphosphonates
Fosamax (alendronate) Actonel (risedronate) Boniva (ibandronate)	70 mg/wk 35 mg/wk 150 mg/mo	Reflux GI distress Myalgias and bone pain in early doses	GI bleeding and esophageal erosions Poor absorption Renal clearance of intact drug (need good renal function or drug accumulates)	Affects osteoclast function and number Stops bone loss
IV Bisphosphonates
Aredia (pamidronate) Zometa (zoledronic acid) Boniva (ibandronate)	90 mg q 3 mo 4 mg/yr 3 mg q 3 mo	Myalgias and bone pain with initial doses	Rare cases of osteonecrosis of the jaw	Affects osteoclast function and number Stops bone loss
SERM (selective estrogen receptor modulator)
Evista (Raloxifene)	60 mg/day	Leg cramps Hot flashes	Increased risk of deep vein thrombosis in first 4 months of dosing Cardiovascular neutral Breast cancer protective Use only in postmenopausal women	Returns bone dynamics to premenopausal pattern Stops bone loss
Estrogen (with progesterone)
Prempro	0.625 mg/2.5 mg 0.45 mg/1.5 mg 0.3 mg/1.5 mg	Persistent menstrual bleeding Increased risk heart attack, stroke, pulmonary embolus, invasive breast cancer	Use lowest effective dose to manage postmenopausal symptoms.	Return to premenopausal bone dynamics Protection against hip and vertebral fracture
Estrogen
Premarin	0.625 mg 0.45 mg 0.3 mg 1.25 mg 0.9 mg	Increased risk of stroke	Increased risk of endometrial cancer in women with intact uterus No increased risk of breast cancer Bone benefits equal at all doses; use lowest effective dose for other symptoms	Return to premenopausal bone dynamics Protection against hip and vertebral fracture
1-34 PTH
Forteo (teriparatide)	20 mcg/day SC for maximum of 2 yr	Dizziness and myalgias in first 4 to 6 weeks of use in some patients	Black Box Warning with increased rate of osteosarcoma in rats	Stimulates osteoblastic bone formation greater than osteoclastic bone resorption

Calcium and vitamin D
Bisphosphonates
Selective estrogen receptor modulators (SERM)
Calcitonin
PTH treatment
Estrogen

Fall prevention: hip protectors
- Decrease hip fracture risk up to 93%
- Poor compliance with wear (31%)
Balance training: Tai Chi, dancing
Exercise

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- Strength
- Weight bearing
  - Especially important in children and young adults (can see gains with increased activity)
  - In older adults it helps to slow bone loss (no gains, but maintenance or slower loss).
- Endurance
- Avoid abdominal crunches and limit weight lifting to low weights (<10 lbs).

Pharmacologic

Calcium and vitamin D supplementation
- Necessary for all patients
- Not sufficient alone to treat osteoporosis in adults
- Useful alone in prevention and in children
- Given in divided doses of 500 to 600 mg calcium per dose
- Two types of calcium supplements available
  - Calcium carbonate (Oscal, Caltrate, Tums)
    - Needs acid environment to dissolve completely
      - Beware use in elderly (many people over age 70 are achloridic).
      - Beware H₂ blockers.
  - Calcium citrate (Citrical)
    - Dissolves in absence of acid
    - Increased risk of kidney stones in the small percentage of patients who get citrate-based stones (most get oxalate stones)
    - Clinical significance of difference not completely clear

Bisphosphonates (Table 10-2)

Analogues of pyrophosphate

Mode of action

Bind to surface of hydroxyapatite crystals
Inhibit crystal resorption
Inhibit mevalonate pathway and protein prenylation
Reduce production of protons and lysosomal enzymes by osteoclasts
First-generation forms also inhibit bone formation (not used clinically anymore).
Second and third generations inhibit resorption 1,000 times greater than they inhibit formation.

Recent data show importance of cumulative dose.

Table 10-2 Bisphosphonates

Brand Name	Generic Name	Dosage
Fosamax	Alendronate	70 mg once weekly
Actonel	Risedronate	35 mg once weekly
Boniva	Ibandronate	150 mg once monthly
Zometa*	Zoledronic acid	4 mg IV once yearly
*Not currently approved by the U.S. Food and Drug Administration for this indication

Allows for weekly, monthly, quarterly, or yearly dosing for effect

Not metabolized; excreted in urine intact
Long half-life (estimated 6 to 10 years)
Cessation of treatment does not lead to rapid bone loss
Fracture rates decline 50% at spine/hip/wrist after 1 year
Side effects include esophagus irritation
(10% to 15%) and osteonecrosis of jaw occuring at a rate of 1 per
100,000 patient years of drug intake
Used as treatment for men
Used to prevent losses during steroid treatment
Bone mass gains can sometimes be seen in the first 4 years of treatment, but not seen in all patients
- 2% to 4% per year for vertebral body
- 1% to 2% per year for hip

SERM: raloxifene (Evista)
- Antagonist to breast cancer but agonist to bone formation
- Antiestrogens with bone augmentation effects
- Very effective in improving bone mass, preventing vertebral fractures
- Can augment treatment with bisphosphonates (additive effects of both drugs)
- Reduces incidence of breast cancer 50%
- No cardiovascular effects, no increase in cardiovascular complications
- No added risk of uterine cancer
- Not as potent as estrogen therapy
- Dose 60 mg daily
Calcitonin (Miacalcin Nasal Spray)
- Non-sex/non-steroid hormone
- Binds to osteoclasts to decrease activity/number
- Dose 200 units/day sprayed in alternate nostrils
- Analgesic effect with painful vertebral fractures
  - Mechanism unknown; no deleterious effects on healing
- Effective in stabilizing spinal bone mass and decreasing vertebral fractures, but no effect on hip fractures
PTH (Forteo)
- First approved therapy that actually builds significant bone (anabolic agent)
- Daily low-dose injections increase bone mass in animals and humans.
- Increase life span of osteoblasts
- Forteo is amino acids 1–34 of PTH.
  - Dose is 20 mcg daily for 2 years.
  - Spine bone mineral density increases at 6 to 12 months.
  - Hip bone mineral density increases delayed as much as 18 to 24 months
  - Overall bone mass gains of 8% to 15% per year of therapy
- Follow therapy with agents to maintain bone mass (usually bisphosphonates).
- Conflicting evidence about concurrent use with bisphosphonates
  - Some studies show decreased gains with PTH with simultaneous bisphosphonate therapy.
  - Sequential use does not appear to decrease effect.
- Common side effects
  - Myalgias in back and thigh muscles in first month of therapy
    - Not common
    - Resolve after this time frame
  - Dizziness in first 4 to 6 weeks
    - More common in elderly
    - Take before going to bed to decrease fall risk.
    - Generally not a problem after this time frame
- Black Box Warning
  - Contraindications include previous radiation therapy, Paget’s disease, and very young patients
  - In animal studies at higher dosing levels, osteosarcoma developed before death from drug.
    - Significance related to human osteosarcoma unclear
Estrogen
- While not a part of the black box
  warning, as a part of the general warnings from the manufacturer this
  drug should not be used if
  - Bone metastases or a history of skeletal malignancies
  - Metabolic bone diseases other than osteoporosis
  - Pre-existing hypercalcemia
  - Pregnancy and lactation
- Formerly the gold standard for therapy
- Receptors on both osteoblast and osteoclast
- Patients with intact uterus should take progestin/estrogen combination.
  - Unopposed estrogen increases endometrial cancer risk.
- Women’s Health Initiative
  - 16,608 postmenopausal women age 50 to 79 randomized to estrogen 0.625 mg and medroxyprogesterone 2.5 mg/day or placebo
  - Terminated trial 3 years early because threshold for breast cancer events reached and global index showed risk > benefit
  - Unequivocal benefit for reducing hip fractures (hazard ratio [HR] = 0.66)
  - Overall increase in breast cancer (HR = 1.26), cardiovascular events (HR=1.29), strokes (HR= 1.41), and PE (HR=2.13)
- Still used in some women, often at patient’s request due to severe perimenopausal symptoms
  - Lower doses available

Osteomalacia and Rickets

Pathogenesis

Etiology

Nutritional deficiency of vitamin D
- Results in inadequate intestinal calcium absorption
Genetic anomalies
- 1α-hydroxylase deficiency from mutation
- Vitamin D receptor (VDR) mutation
- PHEX gene mutation in X-linked hypophosphatemic rickets

Pathophysiology

Total amount of bone normal; mineralization inadequate

Histology

Bone biopsy
- Widened osteoid seams
- Smudging of tetracycline labels from slow mineralization rate
Growth plate
- Widened growth plate with lack of mineralization in provisional zone of calcification

Epidemiology

Children get rickets (bone and growth plate effected).
Adults get osteomalacia.
Accounts for at least 8% of hip fractures in United States

Classification

Nutritional deficiency more common (calcium/vitamin D)
- Inadequate vitamin D intake/inadequate sun exposure
- Calcium chelators, phosphate binders
- Elderly need more sun exposure for enough vitamin D (impaired hepatic/renal hydroxylation).
- Intestinal malabsorption most common cause
PO₄ disorders
- Renal disease with leakage
- Oncogenic osteomalacia (or tumor-induced osteomalacias)
- X-linked hypophosphatemic rickets
- Renal osteodystrophy

Diagnosis

Clinical Features

Physical Findings

Rickets
- Frontal skull bossing
- Enlarged costochondral junction (rachitic rosary)
- Bowing of long bones
- Delay in eruption of permanent teeth
- Minimal-trauma fractures
Osteomalacia
- Minimal-trauma fractures
- Proximal muscle weakness
- Gait instability

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Laboratory Findings

High PTH
High alkaline phosphatase
Low to normal calcium
Low 25-hydroxy vitamin D
Often normal 1,25-dihydroxy vitamin D

Radiologic Features

Rickets
- Metaphyseal flaring, widened growth plates
- Best seen in distal radius/ulna or around knee
- Loss of provisional zone of calcification
Osteomalacia
- Long bones appear osteopenic.
- Looser lines
  - Stress fractures result in radiodense lines.
  - Prominent on concave side of extremity bows
  - Can see adjacent areas of radiolucency as healing produces unmineralized osteoid (looser zones)

Treatment

Nutritional deficiency
- Short-course, high-dose therapy with vitamin D
  - 50,000 IU vitamin D₂ once weekly or 1,000 IU vitamin D₃ daily for 3 to 6 months
  - Modulate vitamin D dosing depending upon severity.
  - May require chronic higher dosing of vitamin D
  - Recent data show vitamin D₃ supplements are better at maintaining levels than vitamin D₂.
X-linked hypophosphatemic rickets
- Renal tubular defect from mutation in PHEX
- Phosphate loss leaves insufficient levels for mineralization.
- Treat with large doses of phosphate.

Primary Hyperparathyroidism

Pathogenesis

Etiology

Excessive PTH secretion from one or more parathyroid glands

Epidemiology

Female predilection 3:1
Incidence 1 per 500 to 1,000

Pathophysiology

Cells have higher “set point” for sensing elevated serum calcium levels and stopping PTH production.
Oversecretion of PTH
- Affects bones, kidneys, intestine (indirectly by stimulating vitamin D production in kidney)
- Results in hypercalcemia

Genetics

Several possibilities
- Gene rearrangement in PRAD-1 oncogene
- Overexpression of cyclin D1
- Loss of one copy MEN-I tumor suppressor gene on chromosome 11

Classification

Solitary adenoma (80% to 85%)
Four-gland hyperplasia (15% to 20%)
Parathyroid carcinoma (<0.5%)

Diagnosis

Clinical Features

Renal
- Nephrolithiasis
- Nephrocalcinosis (calcium deposition in the renal parenchyma)
- Hypercalciuria
  - >250 mg for women, >300 mg for men
Skeletal
- Bone density losses
- Osteitis fibrosa cystica (brown tumors of long bones)
Laboratory findings
- Diagnosis is made by elevated PTH and elevated calcium
- Other laboratory anomalies include
  hypophosphatemia, hyperphosphaturia, elevated uric acid levels, and
  increased alkaline phosphatase levels.

Radiologic Features

X-ray changes
- Tufts distal phalanges affected first (subperiosteal resorption)
- Radial border of middle phalanges
- More advanced cases show erosion of distal clavicles.
- Brown tumors rare in primary hyperparathyroidism
- Densitometry more sensitive early measurement
- 50% of patients show demineralization, mostly cortical.

Treatment

Surgical excision of adenoma
Excise 3.5 glands with general hypertrophy.

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Medical management
- Patients mildly symptomatic, poor surgical candidates
- Hydration, low calcium intake, osteoclast-inhibiting drugs like bisphosphonates
With treatment, improved bone mass in 2 to 4 years

Renal Osteodystrophy (Secondary Hyperparathyroidism)

Pathophysiology

High PO₄, low 1α hydroxylase leads to low calcium levels.
Hyperplasia of parathyroid glands results in response to chronic low calcium.
Skeletal resistance to the ability of PTH to liberate calcium from the skeleton
Osteomalacia from aluminum toxicity
- From aluminum-based phosphate binders
- Not used since mid-1980s, rarely an issue now
- Most aluminum seen now from environmental exposure
- Disrupts formation of hydroxyapatite crystals and inhibits osteoblasts
Adynamic bone with little bone formation
- Generally also see poor osteoblast function and poor bone formation

Etiology

Combination of secondary
hyperparathyroidism and osteomalacia as a complication of the
metabolism anomalies associated with chronic renal disease

Epidemiology

Rate of end-stage renal disease in United States: 334 per million

Diagnosis

Clinical Features

Begin to appear only with advanced kidney disease
Fragility fractures, especially vertebrae and ribs
Proximal muscle weakness
Spontaneous rupture of tendons with severe hyperparathyroidism can be seen.
β-2 microglobulin amyloidosis can be associated.
Laboratory findings
- Low calcium
- High phosphate
- High PTH
- High creatinine and blood urea nitrogen (BUN)
- Increased urinary phosphate
- Commonly low hydroxy vitamin D and 1,25 dihydroxy vitamin D levels

Radiologic Features

Osteopenia
Fragility fractures
Extraskeletal calcifications
- Vascular
- Periarticular

Treatment

Management of the mineral metabolism
- Administer phosphate binders.
- Treat acidosis.
- Ensure adequate calcium intake.
- Monitor PTH levels.
- Replace vitamins as needed: supplement if 25-hydroxy vitamin D is <30 ng/mL.
Parathyroidectomy for severe hyperparathyroidism.
Surgical treatment of fragility fractures
may also require supplementation with 1,25 dihydroxy Vitamin D in
severe renal failure and dialysis patients.

Osteopetrosis

Pathophysiology

Normal new bone formation, but deficiency of bone/cartilage resorption in one of two ways
- Decreased or absent osteoclasts
- Large numbers of defective osteoclasts present
Diffuse increased skeletal density/marrow space obliteration
- New bone formed is immature, woven bone: bones more fragile and susceptible to fractures

Etiology

Disorder of osteoclast function that
interferes with normal skeletal remodeling and leads to trabecular and
cortical bone thickening

Classification

Four phenotypes
- Adult (tarda) form
  - Majority of patients, normal life span, mild anemia, autosomal dominant
- Congenital (infantile/malignant) form
  - Autosomal recessive, most severe form, death in childhood
  - Anemia, thrombocytopenia, hepatosplenomegaly, immune system compromise, cranial/optic nerve palsies
- Intermediate form
  - Severity between adult/congenital
- Carbonic anhydrase II gene mutation form
  - Autosomal recessive
  - Associated with renal tubular acidosis, cerebral calcifications, and mental retardation
- OL-EDA-ID
  - X-linked trait affecting boys
  - Newly defined
  - Associated osteopetrosis, lymphedema, anhydrotic ectodermal dysplasia
One case report of drug-induced osteopetrosis with large doses of pamidronate

Diagnosis

Clinical Features

Adult form
- Long bone fractures
- Hearing loss
- Carpal tunnel
- Slipped capital femoral epiphysis (SCFE)
- Osteomyelitis of mandible
Infantile form: manifestations in first year
- Nasal stuffiness
- Hearing loss
- Delayed tooth eruption
- Failure to thrive
- Recurrent infections
- Short stature

Radiologic Features

Generalized increase in bone mass
Dense, sclerotic bone
- Thickening of both trabecular and cortical bone
- Can see alternating bands of density in iliac wings
Widened, club-shaped metaphyses (“Ehrlenmeyer flask deformity”)
Vertebrae can have sclerotic bands underlying end plates for “rugger jersey” appearance.

Diagnostic Work-up

Laboratory findings
- Adult form: usually normal laboratory test results
- Infantile form: presence of brain isoenzyme of creatine kinase (BB-CK), secondary hyperparathyroidism, and hypocalcemia
Biopsy findings
- Remnants of primary spongiosa: calcified bars of cartilage within trabeculae

Treatment

Depends on type of disease
Bone marrow transplant
- Infantile form
Gamma interferon can be used for severe forms.
Interest in using PTH and 1,25-dihydroxy vitamin D