Osteogenesis Imperfecta

SK Bhadada, R Santosh, A Bhansali, V Upreti, P Dutta

*Assistant Professor; **Senior Resident; ***Professor and Head, Department of
Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER),
Chandigarh.
Received : 16.9.2008 Accepted : 29.11.2008

Abstract

Background: Osteogenesis imperfecta (OI) is a rare metabolic bone disorder characterized by

increased bone fragility, low bone mass, recurrent fractures and numerous extra-osseus
features. Many patients remain undiagnosed and unattended particularly in developed
countries. Presently, medical management with bisphosphonates has changed the scenario.

Materials and Methods: Twenty consecutive patients of OI were enrolled over a period of
four years. Their clinical features, radiology, and biochemical parameters and treatment
outcome were analysed.

Results: Of the 20 patients, 16 (80%) were male and 4 (20%) were female. Mean age (SD) of
the patients was 20.8 (13.8) years. All the patients had presented with fractures, the number
of fractures per person varying from 1 to 20. Long bones were predominantly involved and
thirteen (65%) had deformities of long bones. Ten (50%) had a positive family history of
fractures after trivial traum. Eleven (55%) patients had dentiginous imperfecta (DI) and ten
(50%) had blue sclerae at presentation. Impaired hearing was present in 1 patient only.
Calcium profile was normal. Nine patients received pamidronate. Fracture frequency and
pain decreased remarkably in these patients.

Conclusion: Patients with OI presented late, predominantly with fracture of long bones,
deformities and blue sclerae. Pamidronate therapy remarkably decreased fractures and pain in
these patients.

Introduction

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility

and low bone mass. The patients have recurrent pathological fractures, which vary in number
and severity depending on the type of OI. (Expanded Sillences classification).1 It is also
associated with numerous extraosseus features like blue sclerae, dentinogenesis imperfecta
(DI), hyperlaxity of skin and ligaments, hearing impairment and presence of wormian bones
in the skull.

Most patients have mutation in one of the two genes encoding alpha chains of collagen type 1
(COL1A1 AND COL1A2). Type I collagen fibers are found in the bones, organ capsules,
fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes
approximately 30% of the human body by weight, is the defective protein in OI.

The traditional management of OI has been physiotherapy, orthosis, orthopedic surgery and
rehabilitation. Presently medical management in the form of bisphosphonates are also in offer
to the patients, though their overall efficacy is still in question. Other treatments include
growth hormone, parathormone, bone marrow transplantion and gene based therapy.1

We report a clinical profile of 20 cases of Osteogenesis Imperfecta from a single centre in

North India.

Patients and methods

Data from 20 consecutive patients of osteogenesis imperfecta who have attended the
Endocrinology department of the Post Graduate Institute of Medical Education and Research
(PGIMER), Chandigarh from January 2003 to June 2007 were analyzed. Osteogenesis
Imperfecta was diagnosed and classified using the modified Sillences classification. Their
demographic details, clinical features, biochemical and radiological abnormalities were noted
and analyzed.

For each patient blood samples were collected for three consecutive days after an 8-hour fast
to estimate serum calcium, inorganic phosphorus, serum alkaline phosphatase, albumin and
creatinine. Reference ranges for serum calcium, inorganic phosphorus, alkaline phosphatase
and albumin were 9-11mg/dl, 3-5 mg/dl, 3-13 King Armstrong Units and 3-5 gram/dl
respectively.). Calcium values were corrected for respective serum albumin level.
Parathormone (iPTH) was measured by immunochemiluminiscence assay (ICMA) (reference
range: 10-69 pg/ml). Serum 25(OH)D was estimated by radioimmunoassay (RIA) (reference
range 9-37 ng/ml) (Diasorin, Stillwater, Minnesota, U.S.A.).

In addition, skeletal survey (radiograph of hands, skull and lumbar spine including pelvis)
and 99mTc MDP whole body bone scan was performed in all. All patients underwent a pure
tone audiometry testing in the Rhinootolaryngology department of our institution. All patients
were also evaluated by a single dental surgeon for dentigenious imperfecta.
Patients with more than one fracture in the last one year at the time of presentation were
offered pamidronate therapy. Nine patients received pamidronate according to protocol (<2
years of age, 0.5 mg/kg/d for three days; 2 to 3 years, 0.75 mg/kg/d for 3 days and greater
than 3 years, 1 mg/kg/d for three days). Calcium profile was repeated for three consecutive
days after therapy. Side effects if any were noted. The same protocol was repeated after 3
months and continued till there was a fracture free period of 1 year.
In all patients who received treatment, clinical features were reviewed, and biochemistry and
radiology were repeated after 3 months to look for healing of fractures.

Statistical analysis

The statistical program for the Social Sciences (Release 10.01, PC Windows; SPSS Inc.,
Chicago IL) was used for the data analysis. Data was expressed as mean SD, until
otherwise specified. p value of <0.05 was considered as significant.

Results

All patients hailed from the neighbouring north Indian states of Punjab, Haryana, Himachal
Pradesh, Jammu and Kashmir, Uttar Pradesh or Rajasthan. Of the 20 patients, 16 (80%) were
male and 4 (20%) were female. Mean age (SD) was 20.8 (13.8) years.

Short stature in children was defined as height below the 3rd percentile of the CDC (Centre
for Disease Control and Prevention) growth charts.2 Short stature in adults was defined as 10
cm below the target height calculated from the mid-parental height. Nine (45%) patients had
short stature by definition.

All (100%) patients presented with fractures, the number of fractures varying from 1 to 20.
Mean (SD) number of fractures by the time of presentation was 6.8 (4.51). Long bones were
predominantly involved, particularly of the lower limb. Out of the 133 fractures recorded,
femoral fractures constituted the majority, followed by the tibiae. One patient had 20
fractures by the time of presentation; all of them involved either of the two femorii. One
patient had fractures of the lumbar vertebrae, besides fractures of the femur (20 fractures in
all). The time taken for the fractures to heal was normal in all cases. Ten (50%) patients had a
positive family history of fractures following trivial trauma. Four of our patients belonged to
the same family. Thirteen (65%) patients had deformities (Fig.1), 4 (20%) had multiple (more
than or equal to 2) deformities.

Dentiginous imperfecta (DI) (Fig. 2) was noted in 11 (55%) of the patients. Two of the four
patients who were less than nine years of age had DI in their temporary teeth. Ten (50%) had
blue sclerae (Fig. 3) at presentation. Joint hyperextensibility was noted in 4 (20%) patients.
Pure tone audiometry revealed impaired hearing (sensorineural) in one (5%) patient only. No
patient had abnormal bruisability and abnormal scarring.

Radiology confirmed the sites of present fractures in all. Extensive callus formation at the site
of previous fractures was noted in 3 (15%) patients. Wormian bones in the skull were noted in
3 (15%) patients. One patient had rhizomelia. Pamidronate lines were observed in few
patients.4

Mean values (SD) for calcium (corrected for serum albumin), phosphate, 25(OH) Vitamin D,
and parathormone were 9.10 (0.32) mg/dl, 4.21(0.07) mg/dl, 24.2(17) ng/dl and 58.53(50)
pg/ml respectively. All the patients had normal calcium and phosphate values. One patient
had severe Vitamin D deficiency (5 ng/ml) as per the Lips classification.3 His corresponding
PTH value was 116 pg/ml.

Nine (45%) patients received pamidronate according to the protocol mentioned.

The mean number of fractures / year (SE) decreased from 1.25 (0.51) to 0.125 (0.125). (p
=0.05). Side effects were noted in two patients. One developed fever for two days and the
other had hypocalcemia on the second day after receiving pamidronate (corrected calcium 8.2
mg/dl),however he did not develop clinical features of the same.

All patients reported considerable relief in pain. Of the 9 patients who had received
pamidronate, 8 have followed up for more than one year. Only one of them had a fracture
(fracture shaft of humerus) after the therapy. In one patient, who had no eruption of
permanent teeth, the same appeared after pamidronate therapy. The same patient also had
corrective surgery for deformities of the lower limbs and had not sustained any fractures after
treatment.

Discussion

The present study has twenty patients of a rare metabolic bone disease from a single centre in
North India. Many of the patients were diagnosed in early adulthood. Nine of them received
pamidronate and responded favorably.

The mean age of our patients was 20.8 (13.8 years). This is higher than the mean ages noted
in most of the studies.5-9,16-23 The reasons for this could probably be due to low index of
suspicion of the disease in early childhood for the milder types of OI (types I, IV, V, VI and
VII). Another reason could be referral bias as our department caters predominantly to adult
endocrinology. No sex predilection has been noted in previous studies.5-9,16-23 We had only
4 females in our series. This could be due to the low number of patients and also probably
due to social stigmata attached to deformities in our country.

Patients with OI most commonly present with pathological fractures. However, these
fractures heal readily, with exuberant callus formation in some variants of OI. The number of
fractures varies according to the severity of disease. Most patients with OI seen clinically are
of type III, where the number of fractures may vary from one to multiple. On the contrary,
mild forms (type 1) may present with no fractures. In severe cases, fractures may be present
in utero , and prenatal screening sonography performed during second trimester may show
bowing of long bones, fractures, limb shortening, and decreased skull echogenicity. In a
compilation of case reviews by Albright JA,17 maximum number of fractures noted was 61
in a 12 year old person. In our study, number of fractures varied between 1 to 20.

Dentiginous imperfecta (DI) may or may not be present in all types of OI. DI was noted in 11
(55%) of our patients. Hearing abnormalities are common especially in type I and most
patients have some degree of hearing loss by the age of 40. In our study however deafness
was found only in one patient. This could probably be due to the low number of patients and
also lower mean age of the patients at presentation. Blue sclerae occur in OI due to defective
collagen in sclerae. It was seen in 10 (50%) patients.

Calcium profile is within the normal limits in OI, unless complicated by fractures or other
diseases like concurrent vitamin D deficiency. The same trend was observed in our study.

There are several specific radiological features reported in OI. They include wormian bones,
beaded ribs, broad bones, numerous fractures with deformities of the long bones,
platyspondylia, cystic metaphyses, popcorn appearance of the growth cartilage, rib fractures,
vertebral fractures, and extensive callus formation. Wormian bones were found in three of our
patients, deformities in 13, and extensive callus formation in 3.

The main stays of treatment of OI remain physiotherapy, orthosis, orthopedic surgery and
rehabilitation. Presently medical management in the form of bisphosphonates is also in offer
to the patients, though their overall efficacy is still in question.24 The other treatments being
investigated are parathyroid hormone,13 bone marrow transplantation14,15 and growth
hormone.10-12.

Bisphosphonates represent a class of drugs that are potent inhibitors of bone resorption and
are widely used to treat children and adults with osteogenesis imperfecta. Bisphosphonates
tried clinically in the treatment of OI are pamidronate, zoledronate, neridronate and
olpadronate.1,8,16,18-23 They have shown to reduce both bone pains and fractures. This has
been attributed to decrease in the bone resorption and increase in the cortical width1,
however there is no effect on collagen. In the present study, bone pain decreased and the
number of fractures per year in every patient also significantly reduced after pamidronate
therapy. Acute side effects include nausea, vomiting, diarrhea, flushing, pyrexia and
hypocalcemia, as was seen in one of our patients who had fever and hypocalcemia.

In conclusion, patients with OI were diagnosed late, predominantly with fracture of long
bones, deformities and blue sclerae. Pamidronate therapy remarkably decreased fractures in
these patients. We need to have a high index of suspicion to diagnose these patients. Timely
intervention can prevent deformity and crippling.

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