The American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) has undertaken the development of systematic reviews to summarize the literature about specific intervention strategies used to assist children with developmental disabilities. These reviews are not best-practice documents or practice guidelines, but rather they gather and present the best evidence for and against the effectiveness of an intervention. Their goal is to present the evidence about interventions in an organized fashion to identify gaps in evidence and help address new research that is needed. The Academy is neither endorsing nor disapproving of an intervention in these reviews. Every effort has been made to assure that AACPDM systematic reviews are free from real or perceived bias. Details of the disclosure and consensus process for AACPDM outcomes reports can be viewed at http://www.aacpdm.org. Nevertheless, the data in an AACPDM systematic review can be interpreted differently, depending on people’s perspectives. Please consider the conclusions presented carefully.
This systematic review of the effects of bisphosphonate treatment in children with osteogenesis imperfecta was conducted using the American Academy for Cerebral Palsy and Developmental Medicine methodology for developing systematic reviews of treatment interventions (Revision 1.1) 2004. Despite a large body of published literature, there have been only eight studies with a sufficiently high level of internal validity to be truly informative. These studies confirm improvement in bone density. Many, but not all studies, demonstrate reduction in fracture rate and enhanced growth. There has been extremely limited evaluation of broader treatment impacts such as deformity, need for orthopedic surgery, pain, functioning, or quality of life. Short-term side effects were minimal. Which medication and dosing regimen is optimal and how long patients should be treated are unclear. This body of evidence would be strengthened by a larger controlled trial, because many studies lacked adequate power to evaluate stated outcomes. These studies do not address the impacts of bisphosphonates in children with milder forms of osteogenesis imperfecta and severe forms that are not due to mutations in the type I pro-collagen gene (e.g. types VII and VIII). Additional research is needed into treatment of infants. More studies evaluating medication choices, optimal dosing, duration of treatment, post-treatment impacts, and long-term side effects are necessary.
American Academy for Cerebral Palsy and Developmental Medicine
International Classification of Functioning, Disability and Health
Level of evidence
Bisphosphonates in osteogenesis imperfecta
Osteogenesis imperfecta (OI) represents a heterogeneous group of conditions characterized by primary bone fragility. The incidence has been estimated at 1–2 per 20 000 births; however, milder forms of OI are probably under-recognized. In the majority of patients, OI results from a genetic mutation in the synthesis of type I collagen, resulting in deficiencies in collagen that can be quantitative (if no protein is produced) or qualitative (if an abnormal protein is produced), or both.1 These deficiencies form an abnormal collagen matrix, creating bone fragility.2 In addition, the badly formed collagen matrix is more susceptible to the body’s normal process of repair. The amount of bone is further reduced by osteoclastic removal of defective collagen rods. Osteoblasts have difficulty making the abnormal collagen and transferring it out of the cell. Despite maximal stimulation, the osteoblasts are unable to deliver proteins at an adequate rate, leading to a failure to synthesize an adequate amount of bone matrix, and osteoporosis results.
Traditionally, patients with OI were classified into four clinical subgroups using the Sillence criteria.3 As our understanding of the genotypic and phenotypic variability has advanced, the utility of this classification has been questioned. Some of the less common syndromes of bone fragility, which have been historically considered to be forms of OI, are not due to collagen defects. For example, type VI OI is due to a mineralization defect, and Bruck syndrome is due to an abnormality in bone specific telopeptidyl hydroxylase. Bone fragility syndromes (related to mutations in type I pro-collagen or mutations in genes encoding for proteins that modify type I pro-collagen, and some of unknown origin) are presented in Table SI (supporting information, published online).
Children with OI have clinical manifestations outside the skeletal system (e.g. hypoacusis, dentigenesis imperfecta, easy bruising, low muscle tone, weakness, central nervous system complications). However, this report is focused on the most prominent symptom, bone fragility.
No cure for OI is likely in the near future.4 The variety of mutations responsible for this condition and the difficulties in control of gene expression make the possibility of gene therapy distant. Bone marrow transplantation has been tried in research settings with limited success.5 Currently, treatment is focused on amelioration of symptoms. Orthopedic surgery is used to strengthen long bones by inserting telescopic rods, to minimize deformity resulting from fractures and to treat deformities such as kyphoscoliosis. Rehabilitation efforts include strengthening, maintaining range, optimizing body alignment, teaching compensatory strategies, and prescribing assistive equipment. Over the past 50 years, various potential medical treatments to improve bone fragility have been touted, come into vogue, and used to treat patients, only to be found unhelpful. These treatments have numbered more than 20, including eight hormones, six mineral compounds, three vitamins, and other miscellaneous treatments. In his 1981 review of the literature, Albright noted ‘waves of interest … with a flurry of activity focused on one medication for 20- to 30-year periods, followed in turn by a slow shift to the next agent.’6 He also noted that many of the proposed treatments had published research reports in which the authors concluded a positive impact (e.g. 15 positive reports for calcitonin, 12 for estrogen, and 14 for vitamin D), but that no study had adequate controls. He cautioned against continued acceptance of potential treatments without adequate evaluation, including comparison with appropriate control populations.
In 1987 Devogelaer et al. first reported the use of a bisphosphonate to treat this condition.7 Its use was based on a hypothesis and extrapolated from bisphosphonate treatment in other bone conditions such as juvenile osteoporosis and Paget disease of bone. The structure of bisphosphonates is based on that of pyrophosphate, a naturally occurring substance known to inhibit bone metabolism. Bisphosphonates have evolved through time from the original compounds (e.g. etidronate) to second- and third-generation aminobisphosphonates such as pamidronate, alendronate, and risedronate. These compounds inhibit farnesyl-pyrophosphate synthase, a key enzyme in the 3-hydroxy-3-methylglutaryl-coenzyme-A reductase pathway required for isophenylation of intracellular proteins.2 This results in failure to attach lipids to proteins that are tethered to the cell membrane of osteoclasts, impairing their biological function and, in high concentrations, causing apoptosis. The bone resorption involved in remodeling is slowed. This results in a favoring of bone formation over resorption during remodeling.
Method of review
This review was conducted using the AACPDM methodology to developing systematic reviews of treatment interventions (revision 1.1) 2004.8
This review is limited to studies in which the intervention was a bisphosphonate and the participants were children (aged <18y at time of treatment) with OI defined by the clinical features shown in Table SI. Studies that involved other populations were included if the data for children with OI were analyzed separately.
The literature search included PubMed (from 1950 to April 2007), CINAHL (from 1982 to April 2007), and the Cochrane Database of Systematic Reviews for studies published in English. The search terms were (osteogenesis imperfecta AND [phosphonate OR bisphosphonate OR pamidronate OR alendronate OR risedronate OR clodronate OR etidronate OR olpadronate OR APD OR zoledronic acid OR neridronate]). Reference lists in studies and review articles and researchers knowledgeable about this intervention were also consulted to identify potentially relevant studies. Abstracts and, if needed, full text of articles were reviewed to exclude publications that were not reports of treatment. Of 109 citations, 70 met inclusion criteria.
Classification of the outcomes
Each study was assigned a level of evidence (LOE) ranging from I to V, according to the study design and methods used, and each outcome of LOE I–III studies was coded by a component of the International Classification of Functioning, Disability and Health (ICF;9Table I). LOE classifications are based on a hierarchy of research designs that range from the greatest to least according to ability of the design alone to reduce bias.10Table II shows the hierarchy by research design used for AACPDM reviews. Even if a study is rated high in terms of LOE, it may still have methodological limitations that could influence the results of the study. Studies rated LOE I–III11–18 were further assessed for the presence or absence of these specific design characteristics. Using the total score from this evaluation, each study was assigned a conduct rating of strong, moderate, or weak. This assessment is based on a series of questions provided in Table III. The conduct ratings of the higher-level studies (LOE I–III)11–18 are provided in Table III so that the reader can determine the strengths and weaknesses of each study. The findings for each outcome of interest in all of the LOE I–III studies are provided in Table IV categorized by component of health.11–18Table V summarizes reported short- and long-term complications of bisphosphonate treatment.19–54 A complete list of all relevant studies considered in this systematic review is provided in Table SII (supporting information published online).7,11–28,32,33,35–45,47–80
|Body function/body structure (BF/BS)||Anatomical parts of the body (organs, limbs, and their components), and physiological and psychological functions of body parts and systems|
|Activity & participation (A&P)||Activity is the execution of a task or action by an individual|
Participation is involvement in a life situation
|Environmental factors (EF)||Environmental factors make up the physical, social, and attitudinal environment in which people live and conduct their lives|
|Level||Intervention (group) studies|
|I||Systematic review of randomized controlled trials (RCTs)|
|Large RCT with narrow confidence intervals (n>100)|
|II||Smaller RCT with wider confidence intervals (n<100)|
|Systematic review of cohort studies|
|Outcomes research (very large ecological studies)|
|III||Cohort study (must have concurrent control group)|
|Systematic review of case–control studies|
|Cohort study without concurrent control group (i.e. with historical control group)|
|Case study or report|
|Expert opinion based on theory or physiological research|
|Sakkers et al.11||II||Strong||Y||Y||Y||Y||N||Y||Y|
|Gatti et al.12||II||Moderate||Y||Y||Y||N||N||Y||Y|
|Letocha et al.13||II||Moderate||Y||Y||Y||N||N||Y||Y|
|Seikaly et al.14||II||Moderate||Y||Y||Y||Y||N||Y||Nc|
|Antoniazzi et al.15||II||Moderate||Y||N||Y||N||N||Y||Y|
|Rauch et al.16||III||Moderate||Y||Y||Y||N||N||Y||Y|
|DiMeglio et al.17,18||II||Weak||N||N||Y||N||N||Y||Y|
|Outcome of interest||Measure||Component of health||Result|
|A. Studies with evidence levels I–III|
|Sakkers et al.11(level II–strong)|
|Bone density||DEXA, spine z-score||BF/BS||Increased in both groups but more so in treated patients (p=0.002)|
|Bone density||Calcaneal bone mineral content and density||BF/BS||No significant difference between groups|
|Vertebral shape||Lumbar vertebral height on plain radiograph||BF/BS||No significant difference between groups|
|Fracture risk||Radiographically confirmed non-vertebral fractures||BF/BS||31% risk reduction in treated group vs placebo (p=0.01)|
|Muscle strength||Hand-held myometer, shoulder abduction, grip, hip flexion||BF/BS||No significant difference between groups|
|Growth||Body/seated height, arm span, head circumference, weight||BF/BS||No significant difference between groups|
|Bone metabolism||Urinary C-telopeptides, deoxypyridinolines||BF/BS||No significant difference between groups|
|Self-care and mobility||PEDI||A&P||No significant difference between groups|
|Ambulation||Bleck scale||A&P||No significant difference between groups|
|Caregiver assistance||PEDI||EF||No significant difference between groups|
|Gatti et al.12(level II–moderate)|
|Bone density||DEXA, spine, femoral neck & hip||BF/BS||Both groups improved, but pamidronate group improved more reaching significance (p<0.05) for lumbar spine at 6 months, and spine, femoral neck, & hip at 12 months|
|Vertebral shape||DEXA, projected area of lumbar vertebrae||BF/BS||Both groups improved, but pamidronate group improved more (p<0.05)|
|Bone metabolism||Alkaline phosphatase (total/bone)||BF/BS||Decreased in both groups. No statistical comparison provided|
|Fracture rate||Clinical report of fracture, non-vertebral||BF/BS||Lower relative risk of any fracture during follow up with pamidronate group (0.6, 95% confidence interval 0.21–1.59)|
|Growth||Height||BF/BS||Increased in both groups, but more substantial in treated group (p<0.05)|
|Letocha et al.13(level II–moderate)|
|Bone density||Lumbar spine DEXA z-score||BF/BS||Increased in treated group (p<0.001) and unchanged in control (intergroup p<0.001)|
|Bone density||Peripheral quantitative computed tomography z-score||BF/BS||Increases in treatment group (not significant vs baseline but p<0.05 vs control group, who had an average decline in z-score)|
|Vertebral shape||Summed L1–L4 midvertebral height, vertebral area||BF/BS||Treated patients had ‘significantly greater rate of increase than controls’ (p value not reported)|
|Fracture rate||Time to first fracture||BF/BS||Longer in treated group but not significantly different from control group (p=0.6)|
|Fracture rate||Change in rate of fractures vs baseline||BF/BS||No intergroup comparison|
|Gross motor function||Brief Assessment of Motor Function scale||A&P||Unchanged|
|Muscle strength||Lower-extremity and abdominal manual muscle strength testing||BF/BS||Unchanged|
|Pain||National Institutes of Health Functional Assessment pain score||BF/BS||Unchanged|
|Bone metabolism||Bone-specific alkaline phosphatase, osteocalcin, procallagen peptide type I||BF/BS||Unchanged|
|Seikaly et al.14(level II–moderate)|
|Bone density||Vertebral DEXA||BF/BS||Improved in treatment phase (p<0.01)|
|Mobility||PEDI||A&P||Improved in treatment and placebo phases (difference not significant)|
|Self-care||WeeFIM||A&P||More improvement in treatment phase (p<0.01)|
|Well-being||Not specified||A&P||Improved in both phases but more so during treatment (p<0.0001)|
|Pain||Not specified||BF/BS||Reduced during treatment phase and increased during placebo phase (p<0.001)|
|Pain||Days per week of analgesic use||BF/BS||Reduced analgesic use during treatment phase and increased use during placebo phase (p<0.05)|
|Growth/nutrition||Body mass index||BF/BS||Unchanged|
|Bone metabolism||uNTX||BF/BS||Reduced during treatment and placebo phases but more so during treatment (p<0.01)|
|Bone metabolism||Calcium, osteocalcin, PTH, dihydroxy vitamin D, urinary hyroxyproline||BF/BS||Unchanged|
|Antoniazzi et al.15(level II–moderate)|
|Bone metabolism||Serum calcium, phosphate, 25-hydroxy vitamin D, osteocalcin, uCa/uCr, uNTX/uCR||BF/BS||Unchanged except uCa/uCr, uNTX/uCr declined but not significantly vs control|
|Growth/nutrition||Insulin-like growth factor 1||BF/BS||Increased but not significantly vs control|
|Growth/nutrition||Recumbent length z-score||BF/BS||Improved (p<0.05)|
|Growth/nutrition||Weight z-score||BF/BS||Improved (p<0.05)|
|Fracture rate||Clinically identified and radiologically confirmed fractures (excluded vertebral fractures and those identified at delivery)||BF/BS||Reduced (p<0.05, 2.4 vs 6.0 fractures/year)|
|Bone formation||Projected lumbar vertebral area||BF/BS||Improved but not significantly vs control|
|Bone pain||Parent report, method not specified||BF/BS||Reduced but no statistical analysis|
|B. Studies evaluating discontinuation of bisphosphonates|
|Rauch et al.16(level III–moderate)|
|Bone metabolism||Serum alkaline phosphatase, PTH, calcium, vitamin D, phosphorus; uCa, uNTX||BF/BS||Most changes not significant, except for NTX/creatinine which increased off pamidronate (p<0.02)|
|Bone mineral content||Lumbar spine DEXA||BF/BS||Decreased with treatment discontinuation, increased with treatment continuation (p=0.04)|
|Fracture rate||Absolute number of clinical fractures||BF/BS||More fractures in discontinuation group (not significant)|
|Functional status||PEDI||A&P||No change|
|Mobility status||PEDI||A&P||No change|
|Growth||Weight z-score||BF/BS||Gained slightly off pamidronate (not significant vs control)|
|Growth||Height z-score||BF/BS||Declined slightly off pamidronate (not significant vs control)|
|C. Studies comparing different bisphosphonates|
|DiMeglio et al.17(level II–weak)|
|Bone density||Total body and lumber DEXA||BF/BS||No difference between groups|
|Linear growth||Height||BF/BS||No difference between groups|
|Bone metabolism||Alkaline phosphatase (total & bone), uNTX, osteocalcin, intact PTH, vitamin D||BF/BS||No difference between groups|
|Fracture incidence||Radiographically confirmed fractures||BF/BS||No difference between groups|
|DiMeglio and Peacock18(oral alendronate vs intravenous pamidronate)|
|Bone mineral density||Body and lumbar spine bone mineral density||BF/BS||Increased similarly in both groups|
|Bone turnover||BF/BS||Decreased similarly in both groups|
|Fracture incidence||BF/BS||Decreased similarly in both groups (not significant)|
|Growth||BF/BS||Increased similarly in both groups|
|Bishop et al.19||Fever||6|
|Bembi et al.20||Transient hyperthermia||3|
|Fujiwara et al.21||Transient high fever and slight lowering of serum calcium|
|Shaw22||Difficulty with intravenous access||1|
|Astrom and Soderhall23||Transient hypocalcemia||3|
|Restriction in social life of child/family due to monthly hospitalization||3|
|Glorieux et al.24||Acute-phase reaction to first infusion||26|
|Minimal decrease in serum calcium (asymptotic)||NR|
|Back and limb pain||NR|
|Kodama et al.25||Increase in fracture rate when growth hormone was added to treatment||1|
|Plotkin et al.26||Acute-phase reaction with first infusion||9|
|Mild decrease in serum calcium||7|
|Gonzalez et al.27||Hyperthermia, nausea, vomiting, dizziness, mild abdominal pain with first dose|
|Lee et al.28||Transient low-grade fever with first infusion|
|Banerjee et al.29||Low serum calcium (3 patients treated with ‘calcium and vitamin D supplements’)||6|
|Rauch et al.30||Decreased bone remodeling rate ‘not necessarily beneficial in the long-term, as microdamage might accumulate in the bone tissue’||100%|
|Increased calcified cartilage||NR|
|No clinical consequences observed in study but authors felt these should be monitored when treating patients because of potential for harm|
|Chien et al.31||Hypocalcemia with seizure||1|
|Falk et al.32||Hypocalcemia without clinical symptoms during 2 of 57 treatment cycles||2|
|Flu-like syndrome on first infusion||5|
|Non-union at recurrent fracture site||1|
|Grissom and Harcke33||Transient pyrexia, nausea, joint pain||NR|
|Rauch et al.34||Short term: ionized calcium decreased in study group as a whole vs baseline (not requiring treatment, positive Chvostek’s sign in some, no other symptoms); drop in calcium level largest at first infusion vs later treatment intervals; elevated parathyroid hormone with first infusion||Whole group|
|Long term: no change in serum calcium, serum phosphorus decreased with time initially, then stable; parathyroid hormone levels elevated in 7||7|
|Adiyaman et al.35||Elevated blood urea nitrogen without change in renal function or ultrasound||1 of 8|
|Arikoski et al.36||Flu-like reaction with fever and muscle aches, typically with first course||Majority|
|Bin-Abbas et al.37||Sclerotic metaphyseal bands||10 of 10|
|DiMeglio et al.38||Fever||NR|
|Munns et al.39||Worsening respiratory status in infants with pre-existing respiratory compromise||4|
|Munns et al.40||Delayed healing of osteotomies (relative risk 7.29, 95% confidence intervals 2.62–20.3)|
|Zacharin and Kanumakala41||Fever||NR|
|Cho et al.42||Intermittent abdominal discomfort with alendronate; only one patient needed to discontinue treatment||6 of 16|
|DiMeglio et al.17||Fever, myalgias, vomiting||NR|
|Forin et al.43||Fever with first infusion||19 of 29|
|Fever with subsequent infusion||5 of 29|
|Hypocalcemia with tremor treated with intravenous calcium in an infant||1|
|Gatti et al.12||Flu-like illness first infusion||10 of 42|
|Munns et al.44||Decreased bone formation rate per bone surface 17% that of historical controls|
|Mineralized growth plate material in secondary bone|
|Pizones et al.45||Case series showed one case of non-union (causing no functional problems) in seven children with a total of 20 fractures and 24 surgeries involving osteotomy||1 of 7|
|Seikaly et al.14||Mild gastrointestinal intolerance with daily alendronate||2 of 17|
|Ward et al.46||Single dose of alendronate resulted in:|
|Headache||7 of 24|
|Nausea||7 of 24|
|Fever||5 of 24|
|Abdominal pain||6 of 24|
|Symptoms more prominent with oral than intravenous administration|
|Antoniazzi et al.15||Febrile reaction after first infusion; despite young age at first infusion, all infants tolerated the infusion well||9 of 10|
|DiMeglio and Peacock18||Fever, myalgia, vomiting in pamidronate group only||NR|
|El Sobky et al.47||Fever, vomiting, transient bony aches, surgical complications similar in both groups||NR|
|Goksen et al.48||Pyrexia and hypocalcemia after first infusion.||3|
|Land et al.49||Interference with periosteal resorption of unclear clinical significance|
|Vallo et al.50||Decreased plasma calcium and inorganic phosphate in first 3 treatment days (not requiring treatment)||NR|
|Flu-like symptoms with first cycle||6 of 10|
|Zeitlin et al.51||Acute-phase reaction after first infusion||Majority|
|Mild hypocalcemia after first infusion|
|Astrom et al.52||Fever after first infusion||5|
|Choi et al.53||Fever after first infusion||4|
|Land et al.54||Fever and skeletal pain after first infusion||Majority|
|Transient asymptomatic hypocalcemia, increased parathyroid hormone, decreased serum phosphorus, and increased 25-hydroxy vitamin D||NR|
Analysis and discussion of the evidence
1. What evidence exists about the effects of the bisphosphonate intervention in the component of ICF in which it was expected to work, (body function and body structure)?
Seven outcomes about body function and structure are available from studies with LOE I–III.11–16 Changes in bone metabolism markers were not consistent across studies. Increased bone density was documented in the spine, femoral neck, hip (all measured by dual-energy X-ray absorptiometry, DEXA), and tibia (measured by peripheral quantitative computed tomography). These DEXA changes were replicated in many studies. No changes were seen in bone density in the calcaneus measured by ultrasound; however, the validity of this methodology in pediatrics has not been determined. Observed impacts on linear growth were conflicting, with statistically significant positive effects on growth documented in two of five studies. Vertebral shape improvements reached statistical significance in one study. A reduction in non-vertebral fracture rate was demonstrated in several studies and was statistically significant in three studies. The reduction in fracture rate was clinically significant, ranging from 30 to 60%. There was no significant difference between the treatment and control groups on measures of muscle strength. Reductions in pain and analgesic use were documented by Seikaly et al.14 but not replicated by Letocha et al.13
2. What evidence exists about the effects of bisphosphonate intervention in the other components of ICF?
Activity and participation
Positive impacts on self-care and well-being were documented by Seikaly et al.14 However, other studies did not replicate these findings. Several studies evaluated impacts on mobility, ambulation, and functional status and found no statistically significant change.
One study looked at the need for caregiver assistance and found no impact.11
3. What evidence exists for linkages within and across these components?
Several studies support linkages between changes in bone metabolism, bone density or mineral content, and reduced fracture risk.11 One study supports a linkage between bone density improvements, pain reduction, enhanced-self care, and well-being.14
4. What kinds and magnitude of medical complications have been documented?
The many published cohort studies as well as the more recent randomized trials allow monitoring of side effects in a substantial number of patients. It is reassuring that very few serious short-term side effects have been observed. Those seen were generally mild and reversible. The most common short-term side effects were fever and body aches reported with first infusion. Hypocalcemia was reported in numerous studies, but serious complications were reported in only one study. This was a neonate who experienced seizures due to hypocalcemia.31 Deterioration in respiratory function with need for intensive care support has been observed in several infants with pre-existing respiratory compromise.39 Several authors raised concern regarding the difficulties with intravenous access and the impact that recurrent hospitalization might have in the functioning, activity, and environmental-context components of health. In one retrospective study, pamidronate treatment was associated with delayed healing of osteotomy sites after intramedullary rodding procedures.40 A prospective cohort study monitored closely and found no increase in delayed healing compared with historical observations in patients with OI. However, with only eight patients (24 bones surgeries, mean 1.6 [SD 0.84] osteotomies per bone), the study may not be adequately powered to exclude delayed healing as a complication.45 Other short-term side effects are listed in Table V. While osteopetrosis has been reported in one child treated with bisphosphonates, it was not observed in any study in which bisphosphonates were used for treatment of OI or in any population using similar dosing regimens.45,81 The total numbers of patients across studies is not adequate to evaluate very rare but serious side effects such as esophagitis due to alendronate or osteonecrosis.
A small number of children were treated for up to 5 years and a few to 8 years with no reported long-term side effects. One author suggested caution regarding the potential impact of decreased bone remodeling and increased calcified cartilage over the long term.30,81 Urinary excretion of pamidronate has been documented up to 8 years after cessation of treatment, and concerns have been raised regarding the potential for this to affect fetal development in previously treated pregnant women.30,82 One retrospective review looked at outcomes in 24 women treated before pregnancy or in early pregnancy with alendronate and noted no major teratogenesis.83 Biochemical analysis and follow-up of the infants was limited. Munns et al. reported on two infants born to women with OI who received pamidronate before conception,84 and Cabar et al. reported on one infant.85 The mothers suffered no ill effects. In the study by Munns et al.,84 both infants had inherited OI. Neither infant had skeletal modeling abnormalities. One infant had transient asymptomatic hypocalcemia at 24 hours of age (biochemical assessment was not available on the other infant at that age), and one infant had bilateral talipes equinovarus.
5. What is the strength of the evidence?
A large body of research exists relevant to potential impacts of bisphosphonates in OI. The vast majority of this research was completed with study designs that have limited internal validity. These studies have the potential to be misleading, particularly if a systematic uncontrolled variable is affecting results across all studies. Possible systematic confounders include the lack of blinding, lower fracture rates with advancing age, impacts of change in care due to study participation or time, and treatment effects of vitamin D and calcium supplementation. While studies with low levels of internal validity support the potential for a treatment to have a measured impact, research with stronger internal validity is required to confirm these effects.
In the past 3 years, studies that have stronger internal validity have been published with a consistent finding of improved bone density. Reduction of fracture risk has been demonstrated in three of four small, randomized controlled trials and appears to be in the range of 30 to 60%. The extent to which this reduction in fracture risk is clinically important may depend on a particular child’s underlying fracture rate, the severity of the fractures, the pain associated with the fractures, and the invasiveness of procedures needed to manage those fractures. In these studies, potential confounders remain, as the published reports did not describe possible differences between the treatment and control groups with regard to intramedullary rods or external bracing at the time of recruitment or during the study. Additionally, the studies did not include vertebral fractures in their calculation of fracture rate.
Positive impacts on growth, vertebral area, self-care, well-being, and pain were seen in small numbers of patients, but not all studies evaluating these impacts demonstrated improvements. No study reported power calculations, and these small studies likely lacked adequate power to exclude the potential for these positive impacts.
This body of evidence is exceedingly limited in the number of children evaluated in studies with LOE I–III. These research results are based on a total of only 101 treated individuals. The data for treatment of infants are extremely limited, with only five treated infants compared with five untreated infants in a randomized prospective fashion. This body of evidence is neither robust nor comprehensive enough to allow confident generalization to groups of people at large. Furthermore, because studies have been focused on children with more severe disease, this body of research is not informative about the role of bisphosphonates in children with mild type I OI or other forms of OI that are not related to collagen mutations.
Summary and directions for future research
Reduction of bone fracture rate, decrease in pain, and improvements in function and societal participation are the stated goals in bisphosphonate treatment of children who have OI. There have been eight studies with a sufficiently high level of internal validity to be truly informative. These studies confirm improvement in bone density. Many, but not all studies, demonstrate reduction in fracture rate and enhanced growth. Bisphosphonates do not eliminate fracture risk, and they are not a cure for this disease. There has been extremely limited evaluation of broader treatment impacts, such as deformity, need for orthopedic surgery, pain, functioning, or quality of life. Which medication and dosing regimen is optimal and how long patients should be treated are unclear. One study attempted to compare treatment efficacy of different bisphosphonates (i.e. pamidronate and alendronate). No difference was found, but, with only six patients in each treated group, it is likely there was insufficient power to detect a true difference between the groups. Another study provided information on the post-treatment effects of pamidronate and concluded that, at least for 2 years after stopping medication, clinical effects on bone density remain. The potential for causing non-union has been a concern. One study systematically evaluated this and found no increased incidence of non-union; however, it probably lacked adequate power to exclude this complication. Little information is available on long-term outcomes, including side effects.
This body of evidence would be strengthened by a larger controlled trial, because many studies lacked adequate power to evaluate stated outcomes. Studies are needed to evaluate the impact of bisphosphonates in individuals with milder forms of OI and severe forms of OI that are not due to collagen mutations (e.g. types VII and VIII). Additional research is needed into treatment of infants. More studies evaluating medication choices, optimal dosing, duration of treatment, post-treatment impacts, and long-term side effects are necessary. Ideally, these studies should be performed in homogeneous groups (i.e. children of similar ages with the same pathophysiological cause for their bone fragility and similar levels of disease severity). Studies should include information on potential confounders such as intramedullary rodding and external bracing. To be accomplished, these studies would need to be multicentered to allow recruitment of an adequate number of participants. Widespread use of bisphosphonate medication is already occurring, so it may be difficult to perform a randomized controlled trial in patients with moderate to severe OI with an untreated control group. Study designs assigning patients to different dosing regimens should be considered. Given the relatively small number of pediatric patients across studies and limited information regarding pregnancy outcomes in women treated with bisphosphonates, registries to monitor for rare side effects would be informative.