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Mrs. Jones, a 59-year-old patient, lost her first and second molars (#18, 19, 30, and 31) six years ago and has been using a mandibular removable partial denture since then. She decided and had implant surgery 5 months ago. When implants were uncovered, clinical inspection revealed that implants replacing #18, 19 and 30 had failed to osteointegrate. The implants were mobile and had a fibrous connective tissue encapsulating them. She had fractured her left wrist 4 months ago; it is still not fully healed according to the orthopedic surgeon. She had a regular physical check up two years ago but has not seen her physician lately. Recently, she has been an experiencing back pain and headache localized in the temple region; OTC medication seems to help. You suggest that Mrs. Jones go to her internist and have complete physical examination including serology. Mrs. Jones was suspected of suffering from either osteomalacia or osteoporosis. Serology tests showed: Blood glucose (>150 mg %); Lower than normal serum calcium; Lower than normal serum phosphorus; Elevated PTH levels; Elevated alkaline phosphatase levels.

1. What conditions might lead to loss of molars at such a young age?

2. What is the process and mechanism of osteointegration?

3. What types of collagens are present in the bone and what is the process of bone formation?

4. Is a 4-month too short an interval for bone to heal and if so what might be the problem with this repair process?

5. Are symptoms of headaches in the temple region an indication of lack of osteointegration? If so what type of OTC medications might help and what is the mechanism of their action at the biochemical level?

6. Is there any significance to the plasma glucose of 150 mg%?

7. What can be deduced from observed lower than normal plasma calcium and phosphate levels in this patient?

8. Under what conditions is the level of serum PTH elevated and what is the biochemical mechanism of PTH release?

9. Why would the plasma levels of alkaline phosphatase go up in this patient and what is the function of alkaline phosphatase in the process of bone formation?

10. What are distinguishing features of osteoporosis and Osteomalacia?

11. What procedures/tests should have been performed before the implantation procedure?

Reading Material

In addition get information from your text book.

Faculty handout

1. Premature loss of teeth can be due to a variety of causes:

  • Accidents

  • Diabetes

  • Radiation therapy: When malignancies of the orofacial region are treated by means of radiation one of the most common sequelae is xerostomia (dry mouth) due to salivary gland destruction. Xerostomia is responsible for the development of cervical caries. Another complication is osteonecrosis, which in many instances is initiated by severe periodontal involvement. Loss of teeth is the end result of these radiation secondary effects.

  • Hereditary diseases like Acatalasia (an autosomal recessive peroxisomal disorder caused by a complete lack of catalase. It causes periodontal infections. , Chediak-Higashi syndrome (is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis) , cyclic neutropenia (is a form of neutropenia that tends to occur every three weeks and lasting three to six days at a time due to changing rates of cell production by the bone marrow)[1], Dentin dysplasia (is a genetic disorder of teeth, commonly exhibiting an autosomal dominant inheritance. It is characterized by presence of normal enamel but atypical dentin with abnormal pulpal morphology), hypophosphatasia (is a rare, and sometimes fatal metabolic bone disease) vitamin D resistant rickets, Lesch-Nyhan syndrome.

  • Lymphomas and leukemias; soft and hard tissue, benign and malignant neoplasms either primary or metastatic.

  • Other abnormalities like Acrodynia (mercury poisoning), Odontodysplasia deficient formation of enamel) (ghost teeth), Osteomyelitis, Periodontitis and Vit. C deficiency.

2. Osteointegration:
In general, the implant site is filled with blood clot characterized by the presence of high proportion of erythrocytes entrapped in a fibrin network. This is followed by proliferation of vascular structures and migration of fibroblast-like mesenchymal cells into the wound chamber. Osteoblasts then migrate to the implant site within a week and within 4 weeks primary bone spongiosa is formed. This is then replaced by lamellar and/or parallel fibred bone.

Osteointegration was defined as a "direct structural and functional connection between ordered living bone and the surface of a load-carrying implant." Although osteointegration was meant originally to describe a biologic fixation of the titanium dental implants, it is now used to describe the attachment of other materials used for dental and orthopedic applications as well. Analyses of material-bone interface show that osteointegrated implants can have an intervening fibrous layer or direct bone apposition characterized by bone bonding depending on the composition and surface properties of the biomaterial. Biologic factors include the quality of bone. Biomaterial factors include the effect of material composition on the bone-material interface. Areas that need to be considered include determining the correlation between oral bone status and osteoporosis, the effect of gender, age, and endocrine status (e.g., osteoporosis) on implant success or failure, the effect of calcium phosphate coating composition and crystallinity on in vivo performance of implants, the factors contributing to accelerated osteointegration, and development of osteoinductive implants.

3. Bone collagen and process of bone formation

  • There are more than 19 collagens known. The main collagen in bone is type 1but small amounts of collagen type III may also be present.

  • Collagens are synthesized and secreted by a variety of cells. For bone the osteoblasts are the most important cell types.

a. Bone Formation

The process of bone formation (osteogenesis) involves three main steps: 

      • production of the extracellular organic matrix (osteoid); 

      • mineralization of the matrix to form bone

      • and bone remodeling by resorption and reformation. 

The cellular activities of osteoblasts, osteocytes, and osteoclasts are essential to the process. Osteoblasts synthesize the collagenous precursors of bone matrix and also regulate its mineralization. As the process of bone formation progresses, the osteoblasts come to lie in tiny spaces (lacunae) within the surrounding mineralized matrix and are then called osteocytes. The cell processes of osteocytes occupy minute canals (canaliculi), which permit the circulation of tissue fluids. To meet the requirements of skeletal growth and mechanical function, bone undergoes dynamic remodeling by a coupled process of bone resorption by osteoclasts and reformation by osteoblasts.

b. Osteoblasts and Bone Matrix

Osteoblasts are derived from mesenchymal stem cells of the bone marrow stroma. They possess a single nucleus; have a shape that varies from flat to plump, reflecting their level of cellular activity, and in later stages of maturity line up along bone-forming surfaces. Osteoblasts synthesize and lay down collagen 1, which comprises 90-95% of the organic matrix of bone. Osteoblasts also produce osteocalcin -the most abundant non-collagenous protein of bone matrix- and the proteoglycans of ground substance and are rich in alkaline phosphatase, an organic phosphate-splitting enzyme. Osteoblasts have receptors for parathyroid hormone and apparently for estrogen. Hormones, growth factors, physical activity, and other stimuli act mainly through osteoblasts to bring about their effects on bone.

The collagen 1 formed by osteoblasts is typically deposited in parallel or concentric layers to produce mature (lamellar) bone. But when bone is rapidly formed, as in the fetus or certain pathological conditions (fracture callus, fibrous dysplasia, hyperparathyroidism), the collagen is not deposited in a parallel array but in a basket-like weave and is called woven, immature, or primitive bone.

In fully decalcified bone sections, the extracellular matrix stains pink with H+E, similar to collagen elsewhere but with a more homogeneous than fibrillar structure, which latter is easily observed by polarizing microscopy.

c. Bone Mineralization

The main mineral component of bone is an imperfectly crystalline hydroxyapatite [Ca10 (PO4)6(OH) 2], which comprises about ¼ the volume and ½ the mass of normal adult bone. The mineral crystals, as shown by electron microscopy, are deposited along, and in close relation to, the bone collagen fibrils. Calcium and phosphorus (Pi, inorganic phosphate) are, of course, derived from the blood plasma and ultimately from nutritional sources. Vitamin D metabolites and parathyroid hormone (PTH) are important mediators of calcium regulation, and lack of the former or excess of the latter leads to bone mineral depletion. 

Undercalcified bone sections, such as those stained with the von Kossa stain, are best used for the histological study of bone mineral distribution. The extracellular matrix of bone is mineralized soon after its deposition, but a very thin layer of unmineralized matrix is seen on the bone surface, and this is called the osteoid layer or osteoid seam. In some pathological conditions, the thickness and extent of the osteoid layer may be increased (hyperosteoidosis) or decreased. Hyperosteoidosis may be caused by conditions of delayed bone mineralization (as in osteomalacia/rickets resulting from vitamin D deficiency) or of increased bone formation (as in fracture callus, Paget’s disease of bone, etc.).

4. Clinical observations demonstrate high failure rates of implant fixation in osteoporosis. The reduced healing capacity, including impaired bone formation, in osteoporotic humans might be due to defects in mesenchymal stem cells that lead to reduced proliferation and osteoblastic differentiation. Growth factors show remarkable promise as agents that can improve the healing of bone or increase the proliferation and differentiation capacities of mesenchymal stem cells. The attraction of gene-transfer approaches is the unique ability to deliver authentically processed gene products to precise anatomical locations at therapeutic levels for sustained periods of time.

Bisphosphonates (BPs) are used in the treatment of osteoporosis. However, their effects, especially long-term effects, on bone and bone healing are not fully known. Clodronate (dichloromethylene bisphosphonic acid) is a first-generation BP.

5. Headaches in the temple region may be due to lack of integration and inflammation caused by secreted cytokines. Over the counter medications like aspirin inhibit COX-1 and COX-2 (induced due to inflammation) irreversibly and inhibit the production of PGE2.

6. Plasma glucose of 150 mg% (8.3 mM) is indicative of mild form of diabetes. Diabetic individuals are susceptible to slow healing fractures and exhibit high incidence of periodontal disease.

7. It seems that this individual is suffering from osteomalacia (soft bones). In osteomalacia, the osteoid does not mineralize properly and becomes wide and irregular. This causes a decrease in plasma Ca and phosphate levels. To compensate for low plasma Ca, PTH is released from the chief cells of parathyroid gland.

8. PTH level increased in response to low plasma Ca levels. PTH is synthesized as 115 amino acid pre-pro PTH by membrane bound polysomes and processed first to 90 AA pro PTH (- signal peptide) and then to 85 AA PTH which is stored in the secretory granules and then released as needed.

9. Alkaline phosphatase (ALKP) is an enzyme that hydrolyzes

X-P X + Pi; the identity of X is not known.

There are a number of isoenzymes; bone ALKP is relevant one here. It is associated with the calcification of organic matrix. During process of active bone growth, the level of ALKP goes up. This is consistent with osteomalacia where the process of calcification is active.

10. Osteomalacia, Osteoporosis: Osteomalacia: soft bones; Osteoporosis: Low bone mass

Bone stores 99% of body calcium and calcium salts, laid down in a soft protein matrix, are responsible for the hardness of bones. Long-term calcium deficiency leads to bone thinning or osteomalacia. Osteomalacia refers to the reduction of the mineralization of bone.

The problem of demineralization of bone is confused with loss of whole bone tissue (osteoporosis).   A high calcium intake and adequate Vitamin D will promote optimal bone mineralization in youth and decrease the rate of bone-mineral loss in the later postmenopausal period. Lack of Vitamin D in children leads to Rickets-soft, poorly mineralized bone that bends easily. In older women, a high plasma level of vitamin D enhances calcium absorption, whereas high sodium, protein, alcohol and caffeine intakes will cause increased urinary losses and negative calcium balance. Other regulatory changes and/or vitamin D deficiency may alter the balance between calcium absorption from the bowel and excretion from the kidney. 


The term "Osteoporosis" refers to a loss of total bone mass and not just bone thinning due to calcium deficiency. Bone loss in adults increases the risk of bone fractures and may contribute to the loss of teeth in healthy postmenopausal women. Low bone mass in women is attributed to heredity, estrogen deficiency and lack of regular physical activity.

Osteoporosis is more a problem of disuse atrophy, with age-related reduction of bone growth factors than of calcium deficiency itself. Women, fearing the stooped posture of old age, are eager to take milk or calcium supplements. TV ads, promoting calcium ingestion, show the degenerating profiles of an aging woman and are deceptive. Women over 50 years of age show the most bone thinning because of deficiency of anabolic sex hormone production, especially estrogen and declining physical activity. In early menopause, estrogen replacement is effective therapy for conserving bone mass in women.   Daily, weight-bearing exercise is the best method of maintaining bone-growth at any age.

The best answer to the problem of bone tissue loss, if you rule out daily exercise, would be preventive treatment with hormone replacement, taken from age 45 onward. Cyclic estrogen and progesterone supplementation in post-menopausal women is the currently recommended strategy. Progesterone acts in concert with estrogen to increase bone formation, and decrease bone resorption, with a net increase in bone mass and strength. Low dosage estrogen (0.3 mg/d - day 1 to 25 of arbitrary cycle month), a progestin (day 16-25), with 1000 mg of calcium plus other minerals - manganese, copper, zinc - are recommended as part of a treatment program for post-menopausal osteoporosis. Postmenopausal women given calcium alone show progressive bone de-mineralization. Vitamin D is added and doses up to 4000 i.u. per day have been useful postmenopausal women.


Bisphosphonates are a family of drugs used to prevent and treat osteoporosis. There are three bisphosphonates currently approved for use: alendronate (Fosamax ®), etidronate and risedronate.

Bisphosphonates bind permanently to the surfaces of the bones and slow down the osteoclasts (bone-eroding cells). This allows the osteoblasts (bone-building cells) to work more effectively.

All three bisphosphonates increase bone density and prevent fractures of the spine (vertebral fractures). Alendronate and risedronate have also been shown to prevent hip fractures. Studies show alendronate and risedronate to be more effective in treating osteoporosis than etidronate.

Alendronate (Fosamax) 5.0 to 10.0 mg per day prevents osteoporosis in younger postmenopausal women, an alternative therapy for women who cannot take hormone replacement therapy (HRT) and an adjunctive therapy for women on HRT. The drug also prevents steroid induced osteoporosis should be considered for use in all patients who require long-term steroid therapy. 

Calcitonin (salmon hormone nasal spray) has also been effective in reducing spinal fracture rate in women over a 4-year period.

Raloxifene (Evista 60-120 mg/day), an estrogen hormone receptor modulator reduced spinal fracture rates by 38% in a group of postmenopausal women who had one fracture.

Osteoporosis is a reduction in osseous tissue with unchanged skeletal structure. Two distinct forms are recognized:

  • Primary osteoporosis – Here, the regulatory mechanism between the plasma calcium level and parathyroid hormone secretion is disturbed; generally, the entire skeleton is affected. The juvenile form occurs during pregnancy; the senile form appears during menopause (involution osteoporosis).

  • Secondary osteoporosis – It usually starts in the central skeleton and proceeds centrifugally. There are a number of possible triggers: inactivity, e.g. due to paralysis or immobilization, malnutrition (malabsorption, alcoholism), hyperthyroidism, long-term cortisone therapy. Bone density and strength are highest between the ages of 25 and 35: bone buildup and breakdown are roughly in equilibrium, but buildup predominates during the growing years, breakdown after the age of 35 – if the dietary supply and enteric resorption, or hormonal regulation, is inadequate. In advanced age, furthermore, the food’s calcium supply can no longer be utilized fully, while decreasing physical activity and diminished exposure to fresh air (and sunlight!) accelerate bone breakdown.

11. Take the medical and oral history of the patient. All serology tests should be done to determine bone health prior to initiating the implant procedure.

Osteoinduction is the process by which osteogenesis is induced. It is a phenomenon regularly seen in any type of bone healing process. Osteoinduction implies the recruitment of immature cells and the stimulation of these cells to develop into preosteoblasts. In a bone healing situation such as a fracture, the majority of bone healing is dependent on osteoinduction. Osteoconduction means that bone grows on a surface. This phenomenon is regularly seen in the case of bone implants. Implant materials of low biocompatibility such as copper, silver and bone cement shows little or no osteoconduction. Osseointegration is the stable anchorage of an implant achieved by direct bone-to-implant contact. In craniofacial implantology, this mode of anchorage is the only one for which high success rates have been reported. Osseointegration is possible in other parts of the body, but its importance for the anchorage of major arthroplasties is under debate. Ingrowths of bone in a porous-coated prosthesis may or may not represent osseointegration.

Classification of the Main Osteomalacias




Vitamin D deficiency

Dietary deficiency

(Small-bowel disease

25-hydroxyvitamin D2 deficiency

25-hydroxylase abnormality

(Liver disease

1.25 - dihydroxyvitamin D3 deficiency

1-alpha-hydroxylase failure

Renal failure

1-alpha-hydroxylase deficiency

Pseudo-vitamin D deficiency


Decreased tubular phosphate reabsorption


Phosphate depletion

Use of oral phosphate binds

(Nordin BEC, Peacock M. Aaron J et al:  Osteoporosis and osteomalacia.  Clin. Endocrinal Metab 9:177-205, 1980)

Usual Biochemical Abnormalities in Various Types of Osteomalacia





Decreased calcium



Decreased phosphorus



Decreased calcium x phosphorous



Increased alkaline phosphatase



Increased parathyroid hormone



Decreased 25-hydroxyvitamin D3



(Modified from Nordin BEC, Peacock M. Aaron J et al:  Osteoporosis and osteomalacia.  Clin. Endocrinol Metab 9:177-205, 1980)

Table 1. Characteristics of Patients with Osteomalacia Due to Vitamin D Depletion

* The time interval between the diagnosis of underlying gastrointestinal disease and the development of symptoms due to osteomalacia.

Table 2. Clinical Manifestations of Osteomalacia in 17 Patients

Table 3. Biochemical Measurements in 15 Patients with Osteomalacia Due to Vitamin D Depletion* * Two patients were not included because they had received vitamin D and calcium supplementation for 1 to 2 months. All measurements made in serum unless otherwise indicated.
Data from Parfitt et al [5] and Kleerekoper et al [6] from Michigan population.
Adjusted for serum albumin [5].
§ Ratio in urine.

Table 4. Bone Mineral Density before Treatment in Patients with Osteomalacia Due to Vitamin D Depletion

Table 5: Bone Histomorphometric Findings in 17 Patients with Osteomalacia Due to Vitamin D Depletion

* Data from 66 white postmenopausal healthy women [10, 11 and 12].

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