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.

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
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